All Study Guides Genomics Unit 6
🧬 Genomics Unit 6 – Epigenomics and Gene RegulationEpigenomics explores how gene expression changes without altering DNA sequences. It focuses on chemical modifications to DNA and histones that affect chromatin structure and accessibility. These modifications play crucial roles in cell differentiation, development, and disease by regulating gene expression patterns.
DNA methylation, histone acetylation, and methylation are key epigenetic marks. They're reversible and respond to environmental factors like diet and stress. Epigenetic processes contribute to cellular memory and identity maintenance. Dysregulation is linked to various diseases, including cancer and neurodevelopmental disorders.
Got a Unit Test this week? we crunched the numbers and here's the most likely topics on your next test Key Concepts in Epigenomics
Epigenomics studies heritable changes in gene expression not caused by alterations in the DNA sequence itself
Involves chemical modifications to DNA and histone proteins that affect chromatin structure and accessibility
Plays crucial roles in cell differentiation, development, and disease by regulating gene expression patterns
Modifications include DNA methylation, histone acetylation, and histone methylation (H3K4me3, H3K27me3)
Epigenetic marks are reversible and can be dynamically regulated in response to environmental factors (diet, stress)
Contributes to cellular memory, allowing cells to maintain their identity through cell division
Dysregulation of epigenetic processes is associated with various diseases (cancer, neurodevelopmental disorders)
DNA Modifications and Chromatin Structure
DNA methylation occurs at cytosine residues, primarily in the context of CpG dinucleotides
Catalyzed by DNA methyltransferases (DNMT1, DNMT3A, DNMT3B)
Associated with gene silencing and heterochromatin formation
Methylated DNA can recruit methyl-CpG binding domain (MBD) proteins, which further compact chromatin
DNA demethylation can occur passively during replication or actively through the action of TET enzymes
Chromatin exists in two main states: euchromatin (open, transcriptionally active) and heterochromatin (condensed, transcriptionally silent)
Nucleosome positioning and histone variants (H2A.Z, H3.3) also influence chromatin accessibility and gene regulation
Higher-order chromatin structures, such as topologically associating domains (TADs), play a role in gene regulation
Histone Modifications and Their Effects
Histone proteins (H2A, H2B, H3, H4) form the core of nucleosomes, around which DNA is wrapped
Post-translational modifications (PTMs) of histone tails alter chromatin structure and recruit effector proteins
Histone acetylation, catalyzed by histone acetyltransferases (HATs), is associated with active transcription
Acetylation neutralizes the positive charge of lysine residues, weakening histone-DNA interactions
Recognized by bromodomain-containing proteins, which promote transcription
Histone deacetylases (HDACs) remove acetyl groups, leading to chromatin condensation and gene silencing
Histone methylation can have activating or repressive effects depending on the residue and degree of methylation
H3K4me3 is associated with active promoters, while H3K27me3 marks repressed genes
Catalyzed by histone methyltransferases (HMTs) and removed by histone demethylases (HDMs)
Other modifications include phosphorylation, ubiquitination, and sumoylation, each with specific effects on chromatin structure and gene regulation
Gene Regulation Mechanisms
Epigenetic modifications work in concert with transcription factors and regulatory elements to control gene expression
Promoters, located upstream of genes, contain binding sites for transcription factors and RNA polymerase II
Promoter methylation can prevent transcription factor binding and lead to gene silencing
Enhancers are distal regulatory elements that interact with promoters to activate transcription
Marked by H3K4me1 and H3K27ac, and bound by transcriptional activators (p300, CBP)
Insulators, such as CTCF-binding sites, prevent inappropriate interactions between regulatory elements and genes
Non-coding RNAs (lncRNAs, miRNAs) can also regulate gene expression through epigenetic mechanisms
lncRNAs can recruit chromatin-modifying complexes to specific genomic loci
miRNAs can induce chromatin modifications and DNA methylation at target gene promoters
Epigenetic regulation is crucial for cell-type-specific gene expression and maintaining cellular identity
Epigenetic Inheritance and Reprogramming
Epigenetic marks can be inherited through cell division, allowing for the maintenance of gene expression patterns
DNA methylation patterns are faithfully replicated by DNMT1 during DNA replication
Histone modifications are propagated through the action of histone chaperones and modifying enzymes
Transgenerational epigenetic inheritance occurs when epigenetic marks are passed from parents to offspring
Documented in plants and some animal models, but the extent in humans is still debated
Epigenetic reprogramming erases and re-establishes epigenetic marks at specific developmental stages
Occurs in primordial germ cells and early embryos, resetting the epigenome for totipotency
Incomplete reprogramming can lead to epigenetic disorders (Angelman syndrome, Prader-Willi syndrome)
Induced pluripotent stem cells (iPSCs) are generated by epigenetic reprogramming of somatic cells
Overexpression of Yamanaka factors (OCT4, SOX2, KLF4, c-MYC) induces a pluripotent state
Useful for disease modeling, drug screening, and regenerative medicine
Techniques in Epigenomics Research
Bisulfite sequencing is used to map DNA methylation at single-base resolution
Bisulfite treatment converts unmethylated cytosines to uracil, while methylated cytosines remain unchanged
Whole-genome bisulfite sequencing (WGBS) provides a comprehensive view of the methylome
Chromatin immunoprecipitation followed by sequencing (ChIP-seq) identifies histone modification patterns and transcription factor binding sites
Antibodies specific to the modification or factor of interest are used to enrich for associated DNA fragments
Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) maps open chromatin regions
Transposase Tn5 preferentially inserts adapters into accessible chromatin, which can then be sequenced
Chromosome conformation capture techniques (3C, 4C, Hi-C) investigate 3D chromatin interactions
Based on the principle of crosslinking, restriction digestion, and ligation of spatially proximal DNA fragments
Single-cell epigenomics methods (scBS-seq, scATAC-seq) allow for the study of epigenetic heterogeneity within cell populations
Computational tools and databases (ENCODE, Roadmap Epigenomics) are essential for analyzing and interpreting epigenomic data
Applications in Health and Disease
Epigenetic alterations are implicated in various diseases, including cancer, neurological disorders, and autoimmune conditions
Cancer cells often exhibit global hypomethylation and promoter hypermethylation of tumor suppressor genes
Epigenetic biomarkers (SEPT9 methylation in colorectal cancer) can be used for early detection and prognosis
Epigenetic therapies, such as DNMT inhibitors (azacitidine) and HDAC inhibitors (vorinostat), are used to treat certain cancers
Neurodevelopmental disorders (Rett syndrome, fragile X syndrome) are associated with mutations in epigenetic regulators
Epigenetic therapies targeting these pathways are being explored as potential treatments
Epigenetic factors contribute to the pathogenesis of autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus)
Altered DNA methylation patterns and histone modifications are observed in immune cells and target tissues
Epigenetic age, determined by DNA methylation patterns, is a biomarker of biological aging and disease risk
Environmental factors (diet, pollution, stress) can influence the epigenome, contributing to disease susceptibility
Future Directions and Challenges
Developing more precise and targeted epigenetic therapies with fewer side effects
Selective inhibitors of specific epigenetic enzymes (EZH2, DOT1L) are being investigated
Combination therapies targeting multiple epigenetic pathways may improve efficacy
Understanding the role of epigenetics in complex diseases and traits, such as obesity, diabetes, and mental health disorders
Large-scale epigenome-wide association studies (EWAS) can identify disease-associated epigenetic variants
Integrating epigenomic data with other omics data (transcriptomics, proteomics) to elucidate disease mechanisms
Exploring the potential of epigenetic biomarkers for personalized medicine and risk prediction
Epigenetic signatures could guide treatment decisions and monitor disease progression
Investigating the interplay between the epigenome, microbiome, and environment in health and disease
Addressing technical challenges, such as standardization of epigenomic assays and data analysis pipelines
Developing new technologies for single-cell and spatial epigenomics
Improving computational tools for integrative analysis of multi-omics data
Considering ethical implications of epigenetic research, particularly in the context of epigenetic inheritance and environmental justice