16.3 Eukaryotic Epigenetic Gene Regulation
3 min read•june 14, 2024
remodeling and epigenetic gene regulation are crucial for controlling gene expression. These processes involve dynamic changes in DNA accessibility, , and , allowing cells to fine-tune their genetic programs.
Understanding these mechanisms helps explain how cells with identical DNA can have different functions. It also sheds light on how environmental factors can influence gene expression, potentially leading to long-term changes in cellular behavior and disease risk.
Chromatin Remodeling and Epigenetic Gene Regulation
Chromatin remodeling in gene expression
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- Chromatin remodeling involves dynamic changes in chromatin structure that affect gene expression by altering DNA accessibility to transcription factors and RNA polymerase
- represents loosely packed, transcriptionally active regions (active genes), while represents tightly packed, transcriptionally inactive regions (silenced genes)
- () alter nucleosome positioning to expose or conceal regulatory sequences (promoters, enhancers)
- modulates the binding of transcription factors and RNA polymerase to DNA, thus regulating gene expression
- Chromatin remodeling is crucial for cell-type-specific gene expression patterns during development and in response to environmental cues (hormones, stress)
- Distinct chromatin landscapes in different cell types (neurons, muscle cells) allow for tissue-specific gene expression
- Chromatin remodeling regulates key cellular processes such as cell differentiation (stem cell fate), cell cycle progression (G1/S transition), and stress response (heat shock)
Histone modifications and DNA accessibility
- Histones undergo (PTMs) on specific amino acid residues (lysine, serine, threonine) that influence chromatin structure and gene expression
- Common histone PTMs include acetylation, methylation, phosphorylation, and ubiquitination
- Histone modifications occur primarily on the N-terminal tails that protrude from the nucleosome core
- The combination of histone modifications forms a "" that influences gene expression and chromatin structure
- Histone acetylation by (HATs) is associated with increased gene expression
- Acetylation neutralizes the positive charge of lysine residues, weakening histone-DNA interactions and creating a more open chromatin structure
- Acetylated histones facilitate the recruitment of transcription factors (TFIID) and RNA polymerase II to promoters, enhancing transcription
- (HDACs) remove acetyl groups, leading to a more compact chromatin structure and reduced gene expression
- Histone methylation can have activating or repressive effects on gene expression, depending on the residue and the number of methyl groups
- Trimethylation of histone H3 lysine 4 () marks active promoters, while trimethylation of histone H3 lysine 27 () marks repressed genes
- Histone modifications serve as binding sites for chromatin-associated proteins (chromatin remodelers, transcriptional regulators) that further modulate gene expression
DNA methylation in epigenetic regulation
- DNA methylation involves the addition of a methyl group to the 5' carbon of cytosine residues in CpG dinucleotides by (DNMTs)
- , regions with a high density of CpG dinucleotides, are often found in gene promoters
- DNA methylation is generally associated with transcriptional repression and ()
- Methylated CpG islands can directly interfere with transcription factor binding to their recognition sequences
- Methyl-CpG-binding domain (MBD) proteins recognize methylated DNA and recruit HDACs and chromatin remodeling complexes, creating a repressive chromatin state
- DNA methylation is crucial for various biological processes:
- : Parent-of-origin-specific gene expression (, )
- : Dosage compensation in female mammals ()
- : Maintaining genome stability by preventing transposon activation
- Cell differentiation and lineage commitment: Establishing and maintaining cell-type-specific gene expression patterns (pluripotency genes, lineage-specific genes)
- Aberrant DNA methylation patterns are implicated in diseases such as cancer, where tumor suppressor genes may be hypermethylated and silenced, while oncogenes may be hypomethylated and overexpressed
Epigenetic Regulation and the Epigenome
- Epigenetics refers to heritable changes in gene expression that do not involve alterations in the DNA sequence
- The encompasses all epigenetic modifications across the genome, including DNA methylation, histone modifications, and chromatin structure
- is influenced by the epigenetic state of genes and their regulatory regions
- Gene silencing can occur through various epigenetic mechanisms, including DNA methylation, repressive histone modifications, and chromatin compaction
Key Terms to Review (28)
ATP-dependent chromatin remodeling complexes: ATP-dependent chromatin remodeling complexes are protein assemblies that use the energy derived from ATP hydrolysis to alter the structure and accessibility of chromatin. These complexes play a crucial role in regulating gene expression by repositioning, ejecting, or restructuring nucleosomes, which in turn affects how DNA is packaged and made available for transcription and other processes. By modulating chromatin structure, these complexes contribute significantly to eukaryotic epigenetic gene regulation.
Barr body: A Barr body is an inactive X chromosome found in the cells of female mammals, formed through a process called X-inactivation. This mechanism ensures dosage compensation for X-linked genes between males and females, as females have two X chromosomes while males have one. The inactivation is random in each cell, resulting in a mosaic pattern of gene expression across different tissues.
Chromatin: Chromatin is a complex of DNA and protein found in the nucleus of eukaryotic cells that serves to package DNA into a more compact form, allowing for efficient regulation of gene expression and DNA replication. It plays a crucial role in determining the accessibility of DNA for transcription, replication, and repair processes, impacting how genes are expressed and regulated throughout the cell cycle.
CpG islands: CpG islands are regions of DNA that have a high frequency of cytosine (C) and guanine (G) nucleotides, typically found near the promoter regions of genes. These areas play a critical role in regulating gene expression through epigenetic mechanisms, particularly in the context of DNA methylation, which can influence whether genes are turned on or off.
DNA methylation: DNA methylation is a biochemical process involving the addition of a methyl group to the DNA molecule, typically at cytosine bases in the context of CpG dinucleotides. This modification plays a critical role in regulating gene expression by influencing chromatin structure and accessibility, impacting how genes are turned on or off. Through this mechanism, DNA methylation contributes significantly to cellular differentiation, development, and the stability of the genome.
DNA methyltransferases: DNA methyltransferases are a family of enzymes responsible for adding a methyl group to the DNA molecule, specifically to the cytosine bases in the context of CpG dinucleotides. This process, known as DNA methylation, plays a crucial role in the regulation of gene expression and is a key mechanism in epigenetic modifications, influencing cellular processes such as development, differentiation, and response to environmental stimuli.
Epigenetics: Epigenetics refers to the study of heritable changes in gene expression that do not involve alterations to the underlying DNA sequence. This means that while the genetic code remains unchanged, external or environmental factors can influence how genes are turned on or off, impacting an organism's traits and functions.
Epigenome: The epigenome refers to the complete set of chemical modifications to DNA and histone proteins that regulate gene expression without altering the underlying DNA sequence. It plays a crucial role in how genes are turned on or off, influencing cellular function and development in eukaryotic organisms. Changes in the epigenome can result from environmental factors, lifestyle choices, and developmental cues, impacting not only individual cells but also entire organisms across generations.
Euchromatin: Euchromatin is a form of chromatin that is less densely packed and is associated with active gene expression. It is found in regions of DNA that are transcriptionally active, allowing for easier access to the genetic information needed for RNA synthesis. This loose structure facilitates the binding of transcription factors and RNA polymerase, playing a key role in the regulation of gene expression in eukaryotic cells.
Gene silencing: Gene silencing is a biological process that leads to the inhibition or complete shutdown of gene expression. This regulation can occur at various stages, including transcription and translation, and is essential for maintaining cellular homeostasis and responding to environmental signals. It plays a crucial role in processes like development, differentiation, and the suppression of transposable elements.
Genomic imprinting: Genomic imprinting is an epigenetic phenomenon where certain genes are expressed in a parent-of-origin-specific manner. This means that only one allele of a gene is active, depending on whether it was inherited from the mother or the father, while the other allele is silenced. This unique gene regulation plays a crucial role in development, growth, and can influence various traits and disorders.
H19: H19 is a long non-coding RNA gene that plays a critical role in the regulation of gene expression and is involved in various cellular processes such as growth and differentiation. It is an important example of how epigenetic mechanisms, particularly genomic imprinting, can influence developmental biology and disease states. H19 expression is tightly regulated, and its dysregulation has been linked to certain cancers and other health issues.
H3K27me3: H3K27me3 refers to the trimethylation of lysine 27 on histone H3, which is a crucial epigenetic modification that plays a significant role in gene regulation within eukaryotic cells. This modification is often associated with transcriptional repression, marking regions of chromatin that are silenced or not actively expressed. Understanding H3K27me3 is essential as it reflects how genes can be turned off and is involved in developmental processes, cellular differentiation, and the maintenance of cell identity.
H3K4me3: H3K4me3 refers to the trimethylation of the fourth lysine residue on histone H3, a modification that plays a crucial role in eukaryotic gene regulation. This mark is often found in regions of actively transcribed genes, serving as an important indicator of transcriptional activation and influencing chromatin structure and accessibility. By promoting an open chromatin state, H3K4me3 facilitates the binding of transcription factors and other regulatory proteins necessary for gene expression.
Heterochromatin: Heterochromatin refers to a tightly packed form of DNA that is generally transcriptionally inactive, meaning that its genes are not expressed. This condensed structure plays a significant role in the regulation of gene expression and the maintenance of chromosome stability, impacting processes such as cellular differentiation and development.
Histone acetyltransferases: Histone acetyltransferases (HATs) are enzymes that add acetyl groups to the lysine residues on histone proteins, leading to a more relaxed chromatin structure and enhanced gene expression. By modifying histones, HATs play a crucial role in regulating the accessibility of DNA for transcription and are essential for various cellular processes, including differentiation and response to environmental signals.
Histone code: The histone code refers to the hypothesis that specific patterns of chemical modifications on histone proteins, which package DNA in eukaryotic cells, regulate gene expression and contribute to the epigenetic control of genomic functions. This code involves various modifications such as acetylation, methylation, phosphorylation, and ubiquitination, which can influence how tightly or loosely DNA is wrapped around histones, thereby affecting accessibility for transcription and other nuclear processes.
Histone deacetylases: Histone deacetylases (HDACs) are enzymes that remove acetyl groups from the lysine residues on histone proteins, leading to a more compact chromatin structure and generally resulting in the repression of gene expression. By regulating the acetylation status of histones, these enzymes play a crucial role in controlling access to DNA for transcription factors and other regulatory proteins, impacting both epigenetic modifications and transcriptional regulation.
Histone modifications: Histone modifications are chemical alterations to the histone proteins around which DNA is wrapped, influencing gene expression by altering chromatin structure and accessibility. These modifications play a crucial role in regulating epigenetic processes, impacting cellular functions and identity, and are linked to important biological phenomena such as development and disease.
IGF2: IGF2, or Insulin-like Growth Factor 2, is a protein that plays a crucial role in growth and development, particularly during fetal development. This gene is subject to epigenetic regulation, which influences its expression through mechanisms like DNA methylation and histone modifications, resulting in variations that can affect growth and cellular function throughout life.
Methyl-CpG-binding domain proteins: Methyl-CpG-binding domain proteins are a group of proteins that specifically recognize and bind to methylated cytosines in DNA, particularly within the context of CpG dinucleotides. These proteins play a crucial role in the regulation of gene expression by mediating epigenetic changes, often leading to transcriptional repression of genes associated with methylated regions, thereby influencing cellular differentiation and development.
Nucleosome repositioning: Nucleosome repositioning refers to the dynamic movement of nucleosomes along DNA, altering the accessibility of specific genomic regions for transcription factors and other regulatory proteins. This process plays a crucial role in the regulation of gene expression by allowing or restricting access to DNA sequences that control transcription, thereby influencing cellular functions and developmental processes.
Packing: Packing is the process by which DNA is tightly wound around histone proteins to form nucleosomes, making up the chromatin structure. This compaction regulates the accessibility of DNA for transcription and other processes.
Post-translational modifications: Post-translational modifications (PTMs) are chemical changes that occur to proteins after they have been synthesized by ribosomes. These modifications can significantly influence protein function, stability, localization, and interactions with other molecules. PTMs are crucial for regulating various biological processes and can affect how genes are expressed and how proteins function within the cell.
SWI/SNF: SWI/SNF is a multi-subunit protein complex that functions as an ATP-dependent chromatin remodeling factor, playing a critical role in regulating gene expression by altering chromatin structure. By moving, evicting, or restructuring nucleosomes, SWI/SNF facilitates access to DNA for transcription factors and other regulatory proteins, influencing both transcription initiation and epigenetic modifications.
Transcriptional regulation: Transcriptional regulation refers to the mechanisms that control the transcription of specific genes, determining when and how much of a gene's product is produced. This process is essential for cell differentiation, development, and responses to environmental signals. Transcriptional regulation involves various factors including transcription factors, enhancers, silencers, and epigenetic modifications that interact with DNA to influence gene expression.
Transposable element silencing: Transposable element silencing refers to the regulatory mechanisms that suppress the activity and expression of transposable elements, which are DNA sequences capable of changing their position within the genome. This silencing is crucial for maintaining genomic stability and preventing detrimental effects such as insertion mutations or chromosomal rearrangements, particularly in the context of eukaryotic gene regulation.
X-chromosome inactivation: X-chromosome inactivation is a process in female mammals where one of the two X chromosomes is randomly silenced during early development, ensuring dosage compensation between males (who have one X chromosome) and females (who have two). This epigenetic regulation plays a crucial role in maintaining balance in gene expression from the X chromosome, which is significant for normal development and functioning.