From Valencia’s Estación del Norte (North Station), you can take a C1 regional train to Cullera, which takes about 30 minutes. The Cullera train station is located around 2 kilometers from the town center, so it takes about 20 minutes on foot or 10 minutes by bus to reach downtown.
Once you arrive in the town center, you’ll immediately feel the charm of a small Spanish town—with quaint buildings and well-developed bike paths. The castle perched on a small hill (more of a hill than a mountain) enhances this peaceful atmosphere.
Walking Up to the Castle
The walk to the castle is not difficult at all. If you head straight toward the hill, the path is easy to find. On the way, you’ll pass by white-painted houses reminiscent of Santorini and encounter alcázar-style architecture that evokes the feel of Granada. The streets have that cozy, intricate character similar to those in Granada.
Inside the castle, you can even see an old office that was once used for administrative work. The view of Cullera from this room is absolutely stunning. Now that the room is no longer in use, I found it peaceful to see that a cat had taken over the space for napping.
Spending the night in Cullera may not be necessary, but if you’re visiting Valencia and looking for a nice nearby excursion, this town offers a humble charm that’s worth experiencing. Since it’s also a beachside town, it would be a good summer getaway where you could enjoy the sea and relax at a coastal hotel.
If you’re not particularly interested in swimming, a day trip might be the best way to enjoy Cullera.
Suggested Day Trip Plan
Valencia North Station → (30 min train) → Cullera Station
Cullera Station → (10 min bus) → Cullera Town Center
Explore Cullera Castle (~2 hours)
Lunch (~1 hour)
Beach Walk (~1 hour)
Return to Valencia
This itinerary should give you a well-rounded and satisfying day trip.
Lunch Recommendation
As a coastal resort town, Cullera’s restaurant prices are a bit on the higher side. However, just like I mentioned in my previous post about eating smart in Spain, using the set lunch menu (menú del día) is a great way to get good quality food at a reasonable price.
A restaurant I highly recommend is Sociedad Musical Instructiva Santa Cecilia. According to Google Maps, it has a 4.5-star rating from 415 reviews, making it a trustworthy choice. They offer a lunch menu for 15.90 euros, which includes:
Starter
Main dish
Drink
Dessert
I ordered Andalusian-style fried baby squid (chopitos) and monkfish-shrimp stew, followed by a horchata cake for dessert. The portion of the fried squid was enormous—almost like they fried an entire squid body—and the stew reminded me of a spicy fish soup, but without the spiciness and with a saltier flavor.
The horchata cake was absolutely delicious. If I ever visit Cullera again, I would definitely return to this restaurant.
If you’re in Valencia and looking to explore a charming nearby town, Cullera is a great option. I highly recommend giving it a visit!
Spain’s mealtimes are quite unique—and often a source of frustration for many travelers. Typical Spanish meal times are:
Breakfast: 9:00 AM – 12:00 PM
Lunch: 1:30 PM – 3:00 PM
Dinner: 8:30 PM – 12:00 AM
Almost all restaurants operate according to this schedule. Especially between lunch and dinner, most restaurants take a break, so it’s nearly impossible to find a place open around 6–7 PM, which is a common dinnertime.
This late mealtime schedule may have developed as a cultural adaptation to the hot southern European climate, where people avoid activity during the peak heat of the day. Another important factor is that Spain follows the same time zone as Germany and France, rather than the UK—even though it’s geographically closer to London. This change was imposed by Spain’s former dictator Franco. As a result, people in Spain adapted the clock to fit their habits, rather than adjusting their habits to fit the clock. So in reality, it’s not that Spaniards eat extremely late—it’s more about the official time being out of sync.
Smart Eating in Spain
If you want to eat smarter and more affordably while traveling in Spain, remembering local mealtimes is essential. Spanish locals eat according to these times, and many restaurants offer affordable set menus during those hours.
Breakfast: 9:00 AM – 12:00 PM
This is typically a brunch period. If you go to a non-touristy, local restaurant during this time, you can often get a sandwich (bocadillo) + a drink (beer, wine, soft drink, or water) + coffee (espresso or café con leche) for about 6–8 euros.
Olives, pickles, and peanuts are often provided for free. If you time it right, you can enjoy a very budget-friendly breakfast.
Lunch: 1:30 PM – 3:00 PM
Many restaurants offer a set lunch menu—known to have originated under Franco. It usually includes:
Starter (Menu 1)
Main dish (Menu 2)
Dessert
Drink
All of this typically costs 12–16 euros, offering excellent value for money. It’s strongly recommended to check whether a restaurant offers this “menú del día” before entering. Many dishes are available to choose from, and the quality is generally very good. If you look at Google ratings and menu photos beforehand, you’re likely to find a great spot.
Dinner: After 8:00 PM
There usually aren’t any special deals or set menus at dinner—you’ll pay full price. If you’re traveling on a budget, you can make do with bread, jamón, salad, and other items from a bakery or supermarket. Also, keep in mind that most restaurants don’t open before 8:00 PM, so plan accordingly.
Avoid Tourist Traps
Spain is a major tourist destination, and unfortunately, scams and overcharging are more common than you might expect. Always check Google Maps before entering a restaurant. Aim for places with at least 4.0–4.4 stars and read the reviews. Some bad restaurants charge foreigners more by giving them different menus with higher prices.
Avoid restaurants that aggressively try to bring in customers or are located right next to major tourist spots. Instead, choose places where locals eat.
A good strategy is to search for restaurants rated 4.4 or higher on Google, mark several options, and go to one of them—even if there’s a wait, it’s better than walking into a random place.
Some restaurants charge for bread—usually around 1 euro—so if you don’t plan to eat it, you can politely decline.
Tipping
Tipping is not a common custom in Spain. That said, if the service was excellent, it’s fine to leave a tip.
Seville is at the heart of everything in Andalusia and is the fourth largest city in Spain after Madrid, Barcelona, and Valencia. Located on a plain with the Guadalquivir River running through it, Seville had the geographic advantages to grow into a major city in the water-scarce Andalusian region.
Seville reached its peak during the Age of Exploration. It served as a key port city in this era and was also the city from which Columbus first set sail. At the time, the river level was much higher and ships were smaller, making it suitable as a port city. However, as ships became larger and the river shallower, Seville gradually lost its function as a port and became an inland city.
Seville Cathedral
The place where you can most clearly feel the wealth of this golden age is the Seville Cathedral. Filled with rare artworks and an incredibly beautiful interior, the cathedral evokes the glory of Spain’s Golden Age. The photo shows the view of Seville from the cathedral’s tower.
Inside Seville Cathedral lies the tomb of Christopher Columbus. Since Columbus left a will stating that he would “not set foot on Spanish soil even in death,” his coffin was designed to be held up by four figures representing the Spanish kingdoms of Castile, Aragon, León, and Granada.
This magnificent cathedral is said to be the second largest in Spain, following the Sagrada Familia in Barcelona. It was originally a mosque during the Islamic period and was later converted into a cathedral. The building houses many Christian relics and items used by Spanish royalty for religious ceremonies. Even as someone who is not religious, I felt a sense of awe while viewing the many relics. For those of the Catholic faith, this place would likely be deeply moving.
Plaza de España
Plaza de España is one of Seville’s most famous landmarks. Construction began in 1914 and was completed in 1929. The tiles and wooden elements used in the architecture reflect typical Andalusian design. Through this style, the plaza presents tile murals and Spanish inscriptions that describe the Reconquista and the unique features of major cities across Spain.
The interior of the buildings surrounding Plaza de España is also impressive. The ornate ceiling patterns and the arch-shaped terraces left a strong impression on me.
I visited in the summer, and it was extremely hot. I highly recommend anyone visiting Seville in summer to be prepared for the heat.
Metropol Parasol (Las Setas de Sevilla)
Designed by a German architect and completed in 2011, this building is made entirely of wood. When it was first constructed, it faced a lot of criticism for its exterior appearance. However, after completion, it became one of the must-visit spots in Seville.
Although I didn’t go up to the observation deck, I’ve heard that the nighttime view from the top is amazing.
Seville was one of the last cities I visited on my trip. Despite the extreme heat in summer, it was a deeply impressive city that felt like looking back at Spain’s Golden Age. The image of Seville Cathedral remains one of the most unforgettable sights of my entire trip.
Granada, Spain, means “pomegranate” in Spanish. It is said that the city was named this because its shape resembles a pomegranate. Granada is located in the Andalusia region and was once the capital of the last kingdom of the medieval Islamic dynasty. It is also the place where Queen Isabella completed the Reconquista of Spain. The city is about a 4-hour drive from Valencia. In the summer, temperatures can reach up to 40°C, while in winter, it can drop below freezing. Therefore, when planning your trip, make sure to carefully consider what clothes to bring. (There are even snow-capped mountains near Granada, so it’s definitely not hot all year round.)
Granada preserves a blend of medieval Islamic and Christian influences. With the view of the Alhambra in the distance and the medieval atmosphere of the city, walking through the streets can feel like stepping back into Spain’s medieval and Renaissance periods.
Parking in Granada for Visitors with Rental Cars
If you are renting a car to visit Granada, there is something very important to keep in mind: external vehicles are not allowed in the old town of Granada. If you drive into the old town with your own car, you may have to pay a hefty fine, so be sure to park your car outside the old town. However, from a traveler’s perspective, finding a suitable parking spot can be tricky.
I used a website to find parking in Granada. You can use this site to search for parking locations at your desired spot. The image above shows the result for two days of parking in Granada, and as you can see, the parking fees are not cheap. As mentioned earlier, external vehicles are strictly prohibited in the city center, so I recommend searching for a parking location in advance and choosing a spot with a reasonable location and price.
This site offers much better prices and many discounts compared to trying to find parking on-site, so I highly recommend using https://parclick.com/.
Visiting and Touring the Alhambra
I believe the highlight of Granada is visiting and touring the Alhambra. To enter the Alhambra Palace, you must book your ticket in advance. Before COVID, reservations for the Alhambra would sometimes be fully booked up to three months in advance. So, make sure to reserve your ticket early.
The core of the Alhambra is the palace known as “Palacios Nazaries.” Therefore, make sure to book the Alhambra General / Complete Visit option, and take note of the entry time for Palacios Nazaries so you can enter at the right time.
When purchasing the ticket, the time you select is not for entering the Alhambra itself, but for entering Palacios Nazaries. So you should arrive at the Alhambra at least one hour before your reserved time.
Palacios Nazaries of the Alhambra
You can usually enter Palacios Nazaries up to about one hour after your reserved time. Even if you are late, make sure to ask a staff member for help. Also, a passport is required to enter the Alhambra and all its areas. Do not forget to bring your passport!
This Islamic-style palace, filled with incredibly beautiful patterns, was delicate and intricately designed. It was the residence of the king of the Islamic Kingdom of Granada. When this area was later taken by the Spanish army, the Spanish king ordered that it not be destroyed, and that is why it has been preserved to this day. Many Spanish architects who were impressed by this palace later imitated its design.
The Alhambra is still undergoing restoration, including repainting colors that have faded over time. The design of the inner gardens of the Alhambra was also very impressive. Because Granada is a dry and hot region, water is precious. Yet, through medieval technology, water was made to flow continuously, and the gardens and trees arranged around this water were truly beautiful.
If you plan to visit the Alhambra, I suggest setting aside at least 3 to 4 hours. It’s so beautiful that simply sitting in a shaded area and enjoying the atmosphere is a wonderful experience.
Food Culture in Granada
Some restaurants in Granada have a very unique culture. Though inflation is causing it to disappear, many places still maintain this tradition. In particular, restaurants in Andalusia—especially in Granada—will often serve free tapas with every alcoholic drink or beverage ordered.
The drinks are also very affordable, and the fact that you get food with them is something that surprises and satisfies first-time visitors.
Unfortunately, due to inflation, the amount or availability of these free tapas has started to decrease or disappear in some places. So if you’re visiting Granada before inflation settles down, don’t expect every restaurant to serve free tapas automatically. Be sure to check Google Maps and choose a good place in advance.
The restaurant in the photo is one that always has people lining up to eat. Apparently, there’s a separate section where you receive free tapas with drinks. I personally just paid and ordered my food, and it was very tasty.
Flamenco Performance
Flamenco, which originated in Andalusia, can be enjoyed at many venues in Granada. It’s said that Flamenco shows in Granada are among the most affordable in Spain. I booked my ticket through the GetYourGuide app:
The above links show the reservation and location of the Flamenco performance I attended.
I was very satisfied with the experience. If you’re visiting Granada, I definitely recommend seeing a Flamenco show! During the peak moments of the performance, it’s common for audience members to shout “Olé!”—so don’t be surprised if someone does! And of course, you can shout “Olé!” too!
If I had to choose the best travel destination in Spain, I would confidently say Granada. The city itself is incredibly beautiful, full of history, with the breathtaking Alhambra and plenty to see. On top of that, the delicious and affordable food makes everything come together perfectly.
If I get the chance, I would love to visit Granada again. I truly recommend that you go—it’s absolutely worth it!
Though relatively unknown among Korean travelers, Olite is a beloved destination for Spaniards and European tourists. When I first arrived, I was amazed by the number of international visitors and couldn’t help but wonder how they had all discovered this hidden treasure.
This is a map showing the location of Olite, Navarre, Spain.
Located about two hours north of Zaragoza by car, Olite is a small town that seems straight out of a medieval fairytale. The moment I entered, I was struck by its strong Renaissance and medieval charm—especially the castle that instantly reminded me of Hogwarts from Harry Potter.
Here are a few reasons why I strongly recommend visiting Olite:
The castle is absolutely stunning. Truly, one of the most enchanting castles I’ve seen—it gives off major Hogwarts vibes.
The region is famous for its wine.
The entire village, not just the castle, is picturesque and atmospheric.
You can take a beautiful photo anywhere—this place is Instagram heaven.
The Castle of Olite: A Royal Masterpiece
The Olite castle
The majestic castle you see in the center of town was once the royal palace of the Kingdom of Navarre. During the time when most of Spain was under Islamic rule, Navarre—along with Castile and Aragon—was one of the Christian kingdoms that persisted in the north.
From the main square, you can easily spot the castle. I strongly recommend going inside—tickets were around €10 with a student discount. It’s important to book your visit in advance and arrive at your designated time slot, as the number of visitors is usually high. Once you’re inside, however, there’s no time limit—you can explore at your own pace.
Each watchtower is accessible, and as you climb up, the view opens up to the entire town of Olite. Standing atop the castle, gazing out over the rooftops, I felt as though I had become royalty myself. It was one of those rare moments that stir your imagination endlessly.
Just be careful—some stairways are narrow, and with excited kids running around, it’s good to stay alert. Also, it’s quite windy up top, so hold on to your hats!
The castle’s interior is beautiful, but the view from outside is just as breathtaking. This is truly one of those places that feels like a well-kept secret among locals.
A Castle with a Basque Touch
Interestingly, Basque is also spoken in this region. The architecture reflects a mix of local traditions and Renaissance influences, giving it a unique charm that’s hard to find elsewhere.
If you’ve ever dreamed of walking through a Renaissance-era castle with a touch of Basque flair, Olite is your destination. Don’t miss the chance to take a step back in time in this magical corner of Spain.
Albarracín is a small town located about 30 minutes by car from Teruel. Once selected on Instagram as one of Spain’s most beautiful hidden towns, it remains a relatively undiscovered gem, especially among international travelers. With a population of around 1,000, this village is home to architecture dating back to the medieval Kingdom of Aragón.
I visited Albarracín just before sunset. Driving through wide plateaus and winding mountain roads from Teruel, I eventually arrived at a quiet, pink-hued village nestled in the hills. The homes and buildings, built in medieval times, looked almost as if they might crumble at any moment—adding to their historic charm.
From the ruins of a nearby castle, you can enjoy a breathtaking panoramic view of the village. There are no towering buildings or flashy architecture here—just humble, distinctive structures that speak of a simpler, older way of life. Unlike the grandeur of Madrid or Barcelona, Albarracín offers a glimpse into the lives of ordinary people in medieval Spain.
Like Stepping into the Middle Ages
Walking through the narrow alleyways of Albarracín felt like traveling back in time. I visited in early October, and with very few people around, the town had an even more hauntingly beautiful atmosphere. The buildings lean slightly inward over the narrow streets, which are dimly lit and quite narrow—creating a mysterious, almost cinematic mood.
(If you’re concerned about safety—don’t worry! This area is safe and well-loved by Spanish tourists who come from all over the country.)
Climbing the Ancient City Walls
The town is surrounded by the remnants of old fortress walls, which you can climb for free. The path is not too steep, and the view from the top offers the best angle for capturing Albarracín’s unique charm. The surrounding mountains are just as stunning, adding to the town’s natural beauty.
Although I only visited as a day trip, I would highly recommend staying overnight if you want to fully immerse yourself in the feeling of medieval Spain. Spending a night in one of the local hotels might just make you feel like you’ve stepped into another century.
That was my short but unforgettable visit to Albarracín—an authentic and atmospheric journey into Spain’s medieval past.
Teruel is a small and charming city located in the region of Aragón, nestled between Madrid and Valencia, slightly to the north. Sitting at an altitude of 915 meters, the city is perched high on a plateau, giving it a distinct landscape and climate. I visited Teruel by car from Valencia and was constantly in awe of the stunning natural scenery along the way. The bridges in the area, with their elegant arches, reminded me of medieval and Renaissance styles, adding to the romantic atmosphere of the journey.
Teruel is known for its rich cultural heritage, historical architecture, and picturesque surroundings. The city is home to impressive churches, castles, and ancient murals that attract many visitors. Just outside the city, you’ll also find rivers, mountains, and remnants of old Roman roads, making it a perfect destination for both history lovers and nature enthusiasts.
First Impressions of Teruel
The architectural style of Teruel left a deep impression on me. Many of the buildings feature geometric structures—squares, pentagons, hexagons, and octagons—arranged in a visually harmonious way. The mix of Islamic decorative patterns and vibrant colors, combined with Christian and traditional Spanish elements, gave the city a uniquely exotic feel.
I visited in early to mid-October, and although autumn had settled in, the strong sunlight and high elevation made the temperature swing sharply between day and night. Still, the weather was beautiful and added to the charm of the visit.
The Cathedral and the Legend of “Los Amantes de Teruel”
One of the most remarkable aspects of Teruel is its cathedral—Catedral de Santa María de Mediavilla—which holds a fascinating and tragic legend.
The story dates back to the 13th century and tells of two childhood friends, Isabel and Diego. Diego fell deeply in love with Isabel, but because he came from a poor family, Isabel’s father refused to allow them to marry. Determined to win her hand, Diego left for the battlefield, promising to return within five years after earning a fortune.
Isabel waited faithfully, but Diego did not return within the promised time. Believing he had died, she eventually married another man named Pedro. Diego came back shortly afterward, only to find Isabel already wed. Heartbroken, he asked for a final kiss, but Isabel refused—out of loyalty to her marriage—even though she still loved him. Diego collapsed and died from grief on the spot. Overcome with sorrow, Isabel kissed his lifeless body and died as well.
Their remains are said to be preserved in the cathedral, and visitors can view their tombs, which lie beneath statues of the couple. I was so intrigued by the legend that I asked multiple times to make sure I had understood it correctly. The story is well known in Spain and deeply moving to those who hear it.
Inside the cathedral, you’ll also find exceptional examples of Teruel’s architectural mastery. The space is richly adorned with geometric patterns, and the interior structures incorporate various polygonal forms, especially squares and octagons.
테루엘 전설의 두 남녀
Lunch and Local Recommendations
For lunch, I enjoyed a set menu for about €14.50, which included a starter, a main course, dessert, and a drink. While not particularly cheap, the food was delicious and satisfying. The location of the restaurant was convenient, close to the main attractions, and easy to find. Teruel is also known for its wine, so I highly recommend enjoying a glass while you’re there.
Final Thoughts
The legend of Isabel and Diego, combined with the unique architectural style of the city, makes Teruel an unforgettable destination. Their bones are still said to rest in the cathedral, and the story continues to be cherished by Spaniards to this day. After spending a meaningful half-day exploring the city, I moved on to my next destination—but Teruel remains one of the most memorable stops on my journey through Spain.
Just a note: entering the cathedral is only allowed during designated hours and must be done with a guided tour. The tours are conducted in Spanish, so keep that in mind when planning your visit.
Located about 60 kilometers from Valencia, Xàtiva (also spelled Játiva) is a well-known destination among locals and tourists alike. It takes roughly 30 minutes to reach Xàtiva by car from Valencia’s city center, and with frequent train service from Valencia’s main station—usually running every hour—it’s easily accessible for a day trip. I personally stayed in Xàtiva for about three months, and here I’ll share what makes this city special.
The Glory and Decline of Xàtiva
Xàtiva was a prosperous and powerful city from Roman times through the Islamic caliphates and into the Christian Reconquista period. In the 12th century, it became one of the first cities in Europe where the art of paper-making was introduced by the Arabs, making it a center of cultural and intellectual growth during the Renaissance. Today, Xàtiva is a mid-sized city with a population of around 30,000. Despite its reduced political and economic importance, it remains a place of great historical significance and cultural pride for Valencians. Ask anyone from Valencia, and they’ll likely know of Xàtiva—and for good reason.
Xàtiva Castle – Layers of History
The city’s iconic castle complex is built on the remains of fortifications from both the Roman and medieval periods. Strategically located along a route that connected the Iberian Peninsula to Italy, Xàtiva played a key role in ancient military and trade routes. During the Roman era, a fortress known as Castillo Menor was constructed to protect local residents during times of conflict.
Later, during the medieval period, a larger fortress called Castillo Mayor was built to defend against external invasions. As mentioned earlier, this fortress was also used by locals during the War of Spanish Succession in support of the Habsburg claimant, Charles. Climbing up to the castle requires a small entrance fee of around 6 euros, but I believe the views and historical atmosphere are well worth the price.
Castillo Menor
Xàtiva Nightlife and Atmosphere
During my visit , I found the nightlife in Xàtiva to be lively and energetic. Beers and cocktails were reasonably priced—about 3 euros for a beer and 7 euros for a cocktail. The weather was surprisingly warm even in October, making short sleeves comfortable during the day and night. The streets were packed, especially on Friday and Saturday nights, making it nearly impossible to get a table at restaurants without a reservation. Bars and plazas were bustling late into the night, filled with young people and a vibrant social energy. I also felt very safe walking around at night, thanks to Spain’s generally stable and secure public environment.
Christmas in Xàtiva
Where Christmas celebrations typically end on December 25th, the holiday season in Spain extends to January 6th with the celebration of El Día de los Reyes (Three Kings’ Day). In Spain, the Three Kings—also known as the Biblical Magi or Wise Men—are more culturally significant than Santa Claus.
One of the kings is traditionally depicted as African, and interestingly, many locals say he’s their favorite.
Historically, Xàtiva played a tragic role during the War of Spanish Succession (1701–1714). The city supported Charles of Austria in his claim to the throne, but after Philip V emerged victorious, he retaliated against the cities that had opposed him. Xàtiva was burned to the ground, and many of its citizens were killed. The devastation was compounded by a major earthquake, which further accelerated the city’s decline.
If you’re considering a visit to a lesser-known Spanish town, I highly recommend Xàtiva as a rewarding and culturally rich destination.
Gene regulation ensures that, despite all cells having the same genes in all the body cells, cells in specific locations develop unique functions and maintain only those functions. For example, liver cells, kidney cells, and white blood cells all share the same DNA, yet their abilities are expressed differently. This indicates that each cell regulates gene expression in a distinct manner. To achieve this regulation, gene expression is suppressed at the DNA level through various mechanisms.
DNA Methylation
TDNA methylation is an epigenetic mechanism that regulates genes by controlling DNA structures. In this process, a methyl group (-CH₃) is added to cytosine (C) bases, typically at CpG dinucleotides, affecting transcriptional activity. Methylated promoters block transcription factor binding, preventing gene activation. Additionally, Methyl-CpG binding domain (MBD) proteins recruit histone deacetylases (HDACs), leading to chromatin condensation (heterochromatin formation) and transcriptional repression. If these regulatory mechanisms become abnormal, cells may lose their proper function, potentially leading to diseases such as cancer. This explains why, contrary to early expectations that the Human Genome Project would fully unravel the mysteries of the human body, treating diseases like cancer remains extremely challenging even today.
DNA methylation varies in structure across different organisms. For example, when attempting to cut an E. coli plasmid using a restriction enzyme, the presence of methylation on the plasmid may prevent the enzyme from functioning properly. Therefore, it is essential to check the methylation sensitivity of the restriction enzyme before use. If the enzyme is highly sensitive to methylation, it may be necessary to synthesize an unmethylated plasmid via PCR instead of using plasmids synthesized within the cell. There is an example of AatII to show the enzyme blocked by CpG site.
The DNA pin structure is an important mechanism in regulating gene expression as part of chromatin remodeling. DNA forms loop structures by binding with proteins (e.g., CTCF, Cohesin), bringing specific gene regions (such as promoters, enhancers, and silencers) into physical proximity. This is a key component of 3D genome organization, facilitating interactions between enhancers and promoters to activate transcription or, alternatively, forming loops that block transcription factor access, leading to transcriptional repression. Additionally, DNA is divided into structural units called Topologically Associating Domains (TADs), within which genes interact and are expressed. CTCF and Cohesin play crucial roles in loop formation and maintenance, regulating gene expression, while the Mediator Complex promotes the interaction between enhancers and promoters. Increased methylation can hinder the binding of proteins like CTCF, altering the DNA loop structure, which can break the loop between specific enhancers and promoters, leading to decreased gene expression. Conversely, decreased methylation can allow the formation of previously blocked loops, resulting in increased gene expression.
Does the quantity of mRNA perfectly correspond to the amount of protein? Not exactly. The translation of mRNA into protein can be inhibited by very short RNA molecules, such as microRNA (miRNA) and small interfering RNA (siRNA). These regulatory RNAs bind to target mRNA and suppress its translation or promote its degradation, thereby influencing protein production.
What are the differences between miRNA and siRNA? Their mechanisms are quite similar. Both involve specific RNA molecules binding to mRNA, preventing RNA transcriptase from functioning properly. For example, imagine a railway track designed for train wheels; if the track becomes too thick in certain areas, the train will derail instead of following the path smoothly.
miRNA is primarily endogenous, meaning it is naturally produced within cells. It does not perfectly match the target mRNA but binds with slight mismatches in the base sequence. Additionally, miRNA has a broader range of targets, acting somewhat like a grenade, where its inhibitory strength can vary depending on the type of RNA it binds to. On the other hand, siRNA matches the target mRNA perfectly. While it can be naturally produced within cells, it is most commonly synthesized in laboratories and introduced into cells to inhibit specific genes for experimental purposes. Unlike miRNA, siRNA functions like a sniper rifle, precisely targeting and silencing a single gene with high specificity.
Research of miRNA for Diagnosis
This miRNA was a significant topic that won the Nobel Prize in 2024, highlighting its profound importance. However, studying miRNA manually, gene by gene, is not feasible for human eyes and hands alone. Therefore, this field heavily relies on computational programs for research. The ability to process big data is crucial in this context, and it plays a pivotal role in bioinformatics, driving advancements in the field of life sciences. One example is the critical role miRNA plays in the development of brain cells. By measuring the concentration of specific miRNAs, it is possible to assess the normality of a fetus’s brain. For instance, miR-210 and miR-374a are notable examples. These two miRNAs are particularly useful in evaluating the hypoxic conditions in a fetus’s brain, providing valuable insights into fetal brain health.
If we have a precise map of miRNAs, we could identify which miRNAs are deficient in individuals and supplement them accordingly or determine which miRNAs are effective for specific diseases. This could enable disease treatments that are far more specific than chemical-based drugs. Indeed, there have been various attempts to develop drugs using this concept. However, as previously mentioned, miRNAs function like “grenades,” leading to unexpected toxicity in many cases.
On the other hand, siRNA-based approaches, which operate more like “sniper rifles,” have seen greater success, with about six siRNA-based drugs approved by the FDA. In contrast, miRNA-based therapies have been progressing slowly. Challenges remain in delivering miRNAs to precise target cells, managing unexpected cellular toxicity, and evaluating their stability.
According to a paper published in November 2024, some miRNA-based drugs have reached phase 1 or phase 2 clinical trials, but many fail toxicity tests. Recently, the focus has shifted more toward diagnostics. It seems miRNA is being prioritized for diagnostic applications, while siRNA is advancing in the therapeutic field. Understanding miRNA as a tool for diagnosis and siRNA as the therapeutic counterpart provides a clear picture of current trends.
