Name: mef2c and gene control cascades
Uploaded: 2020-11-23T11:47:37.000Z
Duration: 2 min 23 s
Channel: JoVE

תהליכים תאיים מורכבים רבים נשלטים על ידי כמה גורמי שעתוק מרכזיים, הידועים כווסתי שעתוק ראשיים. רגולטורים ראשיים אלה מקדמים או מעכבים שעתוק של קבוצות גנים, כגון אלה הדרושים להתמיינות תאים. 
חלבונים חשובים אלה יכולים לתפקד באופן ישיר או עקיף כדי לווסת ביטוי גנים.
רגולטורי שעתוק ראשיים יכולים להיקשר ישירות לרצפים מווסתים CIS כדי לשלוט בשעתוק של גנים מרובים המעורבים בתגובות תאיות קשורות. 
MyoD הוא וסת שעתוק ראשי הנדרש להתמיינות תאי שריר. הוא נקשר לרצפים של מאות גנים המעורבים בהתפתחות השריר, כולל שרשרת מיוזין כבדה, חלבון מוטורי המצוי בשריר, ודמין, חוט ביניים ספציפי לשריר.
רגולטורי תמלול ראשיים יכולים גם לפעול בעקיפין על ידי קשירה לרצפים CIS-רגולטוריים השולטים בייצור של גורמי שעתוק אחרים. 
MyoD נקשר לרצפים רגולטוריים הגורמים לביטוי של גורמי שעתוק אחרים, כגון גורם משפר ספציפי למיוציטים 2, המווסת גנים נוספים הדרושים להתפתחות ותיקון רקמת שריר.
רגולטורים ראשיים עובדים לעתים קרובות יחד כדי לקדם התמיינות תאים. הרגולטורים הראשיים Oct4 ו- Sox2 עובדים יחד כדי להסדיר את הביטוי של Zfp206. גורם שעתוק זה חייב לבוא לידי ביטוי גבוה בתאי גזע עובריים של עכברים ובני אדם כדי לעורר התמיינות תאים. 
באופן דומה, יחד, PPARγ ו- C/EBPα מעוררים אדיפוציט, או התפתחות תאי שומן על ידי קשירה לאתרי ויסות CIS עבור חלבונים ספציפיים לאדיפוציט. בנוסף, PPARγ ו- C / EBPα נקשרים כל אחד לאתר תקינת תמלול עבור השני ויוצרים לולאת משוב חיובית כדי להגדיל את התמלול במהלך הבידול עוד יותר.

<ol>
	<li>Hernández-Lemus, E., Baca-López, K., & Tovar, H. (2015). מה הופך רגולטור ראשי לתמלול? גישה של ביולוגיה מערכתית. גבולות בפרמקולוגיה, 9, 697.</li>
	<li>צ'אן, ס 'ס' וקייבה, מ' (2013). מהו רגולטור ראשי?. כתב עת למחקר וטיפול בתאי גזע, 3, 114.</li>
	<li>Hernández-Lemus, E., Baca-López, K., Lemus, R., & García-Herrera, R. (2015). תפקידם של רגולטורים ראשיים ברשתות בקרת גנים. arXiv preprint arXiv:1511.09367.</li>
</ol>

מווסתי שעתוק ראשיים

Master Transcription Regulators

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מווסתי שעתוק ראשיים הם חלבונים מווסתים שאחראים בעיקר על ויסות הביטוי של גנים מרובים. לעתים קרובות גנים אלה פועלים יחד כדי להניע תהליך מורכב. הפעלה של מווסת שעתוק ראשי יכול להוביל לשרשרת של הפעלת תעתיק הנחוצה לתוצאה זו. מווסתים אלה יכולים להיקשר ישירות לרצפים הרגולטוריים של הגנים השונים המעורבים, או שהם יכולים לווסת בעקיפין את התעתוק על ידי קישור לרצפים מווסתים של מווסת תעתיק נוספים ולעורר את ייצורם. הביטוי של פנוטיפ מסוים באורגניזם נמצא לעתים קרובות בשליטה של מווסת שעתוק ראשי אחד או שניים. המשמעות של הרגולטורים הללו בתפקודם של אורגניזמים ובביטוי של פנוטיפים חולים הופכים אותם ליעדים אידיאליים למחקר לפיתוח תרופות.

MEF2C הוא מווסת תעתיק ראשי שאחראי בעיקר להתפתחות סרטן השד. הוא שייך למשפחת Mef2 של מפעילי שעתוק האחראים על התמיינות והתפתחות תאים. ישנן מספר מאפיינים אופייניים של MEF2C המדגימים את תפקידו כמווסת שעתוק ראשי. הוא מורכב משני תחומים מחייבי DNA - Mef2 ו-MADS-box. תחום Mef2 ידוע בתפקוד הקישור והדימריזציה בעל הזיקה הגבוהה שלו. ל-MEF2C יש גם אתרי קישור ל-TEAD1, שותף-רגולטור שאחראי על שיפור התעתוק; MAPK7, גורם שעתוק המווסת את התפשטות תאים והתמיינות; EP300, גורם שעתוק המעורב בוויסות של צמיחת תאים וחלוקתם; וכמה היסטונים דהאצטילאזות, כגון HDAC4, HDAC7 ו-HDAC9.

ניתוח ניסיוני הראה כי MEF2C יכול לווסת ישירות גנים רבים האחראים על הפנוטיפ האונקוגני. הוא יכול גם לווסת באופן עקיף על ידי הפעלת גורמי שעתוק אחרים: 1896 גנים ו-2156 אינטראקציות רגולטוריות בגנים מסדר שני ו-5852 ו-18801 אינטראקציות מהסדר השלישי.
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מווסתי שעתוק ראשיים הם חלבוני בקרה האחראים בעיקר לוויסות הביטוי של גנים מרובים. לעתים קרובות אלה ...

Education

JoVE Core

Molecular Biology

ביולוגיה מולקולרית

Unit 1

יחידה 1

Gene Expression

ביטוי גנים

KEY TERMS AND CONCEPTS

מונחים ומושגים מרכזיים

mef2c and gene control cascades

MEF2C is a master transcription regulator that controls gene expression in coordinated cascades. These regulators are proteins that manage the activity of multiple genes that often work together to produce a complex outcome. When a master transcription regulator is activated, it can start a chain of transcriptional activation that supports that outcome.

Master transcription regulators can act in two main ways. They may bind directly to the regulatory sequences of several genes involved in a process. They may also act indirectly by binding to the regulatory sequences of other transcription regulators and increasing their production. In many cases, the expression of a phenotype, or visible trait, is controlled by one or two of these regulators.

MEF2C is an important example because it is mainly responsible for the development of breast cancer. It belongs to the Mef2 family of transcription activators, which are involved in cell differentiation and development. MEF2C has two DNA-binding domains, called Mef2 and MADS-box. The Mef2 domain is known for high-affinity DNA binding and dimerization, which means it can pair with another molecule.

MEF2C also interacts with several partners that help shape its activity. These include TEAD1, a co-regulator that enhances transcription; MAPK7, a transcription factor that regulates cell proliferation and differentiation; EP300, a transcription factor involved in cell growth and division; and histone deacetylases such as HDAC4, HDAC7, and HDAC9. Experimental analysis shows that MEF2C can directly regulate many genes linked to the oncogenic, or cancer-promoting, phenotype. It can also act indirectly by activating other transcription factors, reaching 1896 genes and 2156 regulatory interactions at the second order and 5852 genes and 18801 interactions at the third order.

Because master transcription regulators influence both normal function and disease-related traits, they are important targets for drug development research. MEF2C is one example that shows how a single regulator can drive wide changes in gene activity and help control a disease phenotype.

MEF2C and Gene Control Cascades

cell specific gene expression

How Cells Switch Genes On and Off

Cells switch genes on and off to make different proteins for different jobs. In multicellular organisms, many cell types are built from the same DNA, but they do not use the same genes in the same way. This difference in gene expression helps explain why cells can look and act so differently. Liver cells are a clear example. They help detoxify blood, make bile to help digest fats, and produce proteins needed for metabolism. To do these jobs, liver cells must express a specific set of genes.

regulation of expression occurs at multiple steps

regulation-of-expression-occurs-at-multiple-steps

How Cells Control Gene Expression

Cells control gene expression at several points between DNA and protein. The most common control point is transcription. At this stage, proteins bind to short regulatory DNA sequences and can either increase or reduce transcription of the linked gene. After transcription, a precursor mRNA is made. This pre-mRNA contains exons, which code for protein, and introns, which do not. It must be processed before translation, and splicing removes the introns and joins the exons. Cells can also regulate...

cis-regulatory sequences

How Cis-Regulatory DNA Controls Transcription

Cis-regulatory sequences are short, non-coding DNA segments that control gene transcription. They sit on the same chromosome as the genes they regulate and act as binding sites for transcriptional regulators. In eukaryotes, these proteins help control gene expression patterns in different cell types. These DNA sequences can be close to a gene or thousands of bases away. When they are far from the gene in the DNA sequence, they are often brought close together in space because chromosomes are...

cooperative binding of transcription regulators

cooperative-binding-of-transcription-regulators

How Transcription Factors Bind DNA

Transcriptional regulators bind to cis-regulatory DNA sequences to control gene transcription. These DNA sequences are very short, usually fewer than ten nucleotide pairs long. Because they are so short, the same sequence can appear by chance in many places across the genome. Some regulators can also bind to groups of similar sequences. That raises the chance of random binding even more. To lower this risk, transcription regulators often form dimers, which are pairs of proteins that bind a DNA...

prokaryotic transcriptional activators and repressors

prokaryotic-transcriptional-activators-and-repressors

Operon Control by Activators and Repressors

Operon control in prokaryotes depends on activators and repressors. Prokaryotic genes are often arranged in groups, not one by one like in eukaryotes. Genes that help carry out the same biochemical process are placed together with their regulatory elements. This group is called an operon, and it is transcribed into a single polycistronic mRNA strand. Activators and repressors are DNA-binding proteins that control transcription in an operon. Activators bind near the promoter, which is the site...

operons

Operons in Bacterial Gene Control

Operons help bacteria control groups of genes at the same time. An operon is a set of genes that are regulated together and can be turned on or off as a unit. This shared control helps bacteria respond quickly to changes in their environment. In many operons, a promoter gives RNA polymerase a place to bind and start transcription. The operon also includes a regulatory region that helps control whether the genes are expressed. When conditions change, the cell can use this setup to manage gene...

the eukaryotic promoter region

Eukaryotic Promoter Motifs and Gene Control

The eukaryotic promoter region is a stretch of DNA located upstream of a gene. It includes an RNA polymerase binding site, a transcription start site, and several cis-regulatory sequences. These DNA signals help control when transcription begins. The promoter can be divided into proximal and distal regions. The proximal promoter lies close to the gene and includes cis-regulatory sequences and the core promoter. The core promoter is the RNA polymerase binding site, and it is usually found...

co-activators and co-repressors

Chromatin Control in Gene Transcription

Chromatin control plays a major role in gene transcription in eukaryotes. Gene expression is regulated by several proteins that work together at a gene regulatory site. Some of these proteins bind directly to specific DNA sequences, while co-regulators attach to those regulators but do not bind DNA on their own. Co-regulators can act as co-activators or co-repressors, depending on the complex they join. One co-regulator may even switch roles in different settings. For example, the...

eukaryotic transcription activators

How Transcription Activators Turn Genes On

Transcription activators are proteins that help turn genes on by promoting transcription from DNA to RNA. They often have two parts. One part binds to DNA, and the other part activates transcription. In some proteins, such as the glucocorticoid receptor and MyoD, one domain can do both jobs. The DNA-binding part recognizes specific regulatory sequences on the DNA. These binding domains are grouped into families based on their structure. Common examples include the leucine zipper, zinc finger,...

eukaryotic transcription inhibitors

How Eukaryotic Gene Repressors Work

Eukaryotic gene repressors help turn specific genes off when the cell needs to control growth, development, or other biochemical processes. These DNA-binding proteins regulate gene expression in eukaryotes. Their presence at the right time and place can be triggered by hormones and signals from other cells. Most transcription inhibitors have two main parts. One part binds DNA, and the other is a repressor domain, which helps shut down transcription. Repressor domains can connect with basal...

combinatorial gene control

Gene Expression by Transcription Factor Combinations

Gene expression can depend on combinations of transcription factors working together. In combinatorial gene control, several transcription factors act in a coordinated way to regulate a single gene. If one or more of these factors are missing, the level of gene expression or repression can change a lot. This kind of control helps explain how a relatively small number of transcription factors can regulate a very large number of genes. More than 30,000 genes are controlled by about 2,000 to...

induced pluripotent stem cells

Reprogramming Cells into Stem Cells

Induced pluripotent stem cells are created by reprogramming mature cells back into a stem-cell state. This process shows that specialized cells can be changed into cells with broader developmental potential. The topic is important in biology because it links cell identity, gene control, and stem cell research. These cells begin as ordinary body cells and are pushed to de-differentiate, or lose their specialized features. After reprogramming, they behave like pluripotent stem cells, which means...

master transcription regulators

MEF2C is a master transcription regulator that controls gene expression in coordinated cascades. These regulators are proteins that manage the activity of multiple genes that often work together to produce a complex outcome. When a master transcription regulator is activated, it can start a chain of transcriptional activation that supports that outcome. Master transcription regulators can act in two main ways. They may bind directly to the regulatory sequences of several genes involved in a...

epigenetic regulation

DNA Methylation and Histone Changes

Epigenetic regulation controls gene activity without changing the DNA sequence. It helps determine when genes are turned on or off in a cell. Two major epigenetic mechanisms are DNA methylation and histone modification. DNA methylation adds chemical groups to DNA, while histone changes affect how tightly DNA is packed around histone proteins. These changes can make genes easier or harder to use. In high school biology, epigenetic regulation is important for understanding how cells with the...

genomic imprinting and inheritance

Genomic Imprinting in Human Disease

Genomic imprinting affects how some inherited genes are turned on or off in human cells. Diploid organisms inherit chromosomes from both parents, and each gene usually has two alleles. In most cases, both alleles are expressed. If one allele is missing or mutated, the other can often compensate, but some genes do not work that way. In genomic imprinting, a gene or its regulatory sequence carries chemical tags, such as methyl groups, on the copy inherited from only one parent. These tags are...

key terms and concepts

Explore how MEF2C drives gene expression cascades, binds DNA, and influences breast cancer phenotypes through direct and indirect regulation.

MEF2C and Gene Control Cascades | JoVE K12

molecular biology

JoVE Core Molecular Biology showcases the molecular processes of the cell through clear and concise animated video lessons. Additionally, in scientist-in-action videos, these concepts' application is demonstrated through real experiments in modern laboratories.

MEF2C and Gene Control Cascades

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