Summary of Mendelian Genetics and Epigenetics

## Introduction Epigenetics is the study of molecules and mechanisms that can perpetuate alternative gene activity states in the context of the same DNA sequence. Unlike changes to nucleotide sequence, epigenetic information alters how genes are expressed without modifying the underlying DNA code. This material explains core carriers of epigenetic information, how they are established and inherited, key examples, and practical implications. > Definition: Epigenetics — the set of molecular mechanisms that can maintain alternative gene activity states without altering the DNA nucleotide sequence. ## Core concepts, broken down ### What is inherited in epigenetics? - Genetic inheritance: change in DNA nucleotide sequence transmitted across cell divisions or generations. - Epigenetic inheritance: transmission of regulatory states (chromatin states, DNA modifications, noncoding RNAs, protein assemblies) that affect gene expression without changing DNA sequence. ### Formal definition used here - We use: "the study of molecules and mechanisms that can perpetuate alternative gene activity states in the context of the same DNA sequence." (Cavalli and Heard, Nature 2019) ## Four carriers of epigenetic information We group major epigenetic carriers into four classes. Each has distinct biochemistry and modes of establishment and maintenance. 1) Heterochromatin components - Key mark: **H3K9 trimethylation** on histone H3. - Writers: SUV39 and SETDB1 methyltransferases. - Reader: HP1 (heterochromatin protein 1), which can bind methylated H3K9 and promote chromatin compaction and self-propagation. - Function: gene silencing, formation of compact chromatin domains. 2) Polycomb group proteins - Key marks: **H3K27 trimethylation**, **H2AK119 ubiquitination**. - Recruitment: DNA-binding proteins and noncoding RNAs can recruit Polycomb repressive complexes (PRC1, PRC2). - Function: long-term repression of developmental regulators; can produce mitotically heritable repressed states. 3) Noncoding RNAs - Types: long noncoding RNAs (lncRNAs), small RNAs. - Mechanism: guide chromatin modifiers or DNA methylation machinery to target loci. - Example: **Xist RNA** mediates X-chromosome inactivation by coating the X chromosome and recruiting silencing complexes. 4) DNA methylation - Chemical modification: **5-methylcytosine** (methylation of cytosine in a CG dinucleotide). - Localization: frequent in CpG islands and other CG-rich regions. - Effect: methylation in gene promoters often reduces expression by blocking transcription factor binding and recruiting methyl-binding proteins that promote repression. - Maintenance: DNA maintenance methyltransferases methylate the newly synthesized DNA strand at hemimethylated CpG sites after replication, allowing inheritance of methylation patterns. > Definition: CpG island — a stretch of DNA with a high frequency of CG dinucleotides often found at promoters; methylation state of CpG islands influences transcription. ## How epigenetic states are copied during cell division - DNA methylation: hemimethylated DNA after replication is recognized by maintenance methyltransferases that restore full methylation. - Histone modifications: during replication and chromatin assembly, parental histones bearing marks are redistributed to daughter strands and can help recruit writers to re-establish marks on new histones. - Protein complexes (HP1, Polycomb) can oligomerize and spread, reinforcing local chromatin states. ## Position effect and classic discovery example - Classic experiment in Drosophila: relocating the White gene near heterochromatin led to variegated expression (red and white eye patches) in clones of cells. This positional effect shows chromatin context can silence a gene without changing its sequence. Did you know that relocation of a gene next to heterochromatin can silence it in some daughter cells but not others, producing mosaic phenotypes such as variegated eye color in flies? ## Epigenetic chang