Chromatin modifiers and remodelers: regulators of cellular differentiation
Nearly all cells of an organism share the same genome but show different phenotypes and carry out diverse functions. Individual cell types, which are characterized by distinct gene expression patterns, are generated during development and are then stably maintained. The chromatin state — the packaging of DNA with both histone and non-histone proteins — has marked effects on gene expression and is believed to contribute to the establishment and the maintenance of cell identities. Indeed, developmental transitions are accompanied by dynamic changes in chromatin states. The assembly and the compaction of chromatin are regulated by multiple mechanisms, including DNA modifications (for example, cytosine methylation and cytosine hydroxymethylation), post-translational modifications (PTMs) of histones (for example, phosphorylation, acetylation, methylation and ubiquitylation), the incorporation of histone variants (for example, H2A.Z and H3.3), ATP-dependent chromatin remodelling and non-coding RNA (ncRNA)-mediated pathways. In recent years, substantial progress has been made in understanding the roles of histone modifications and chromatin remodeling in cellular differentiation. PTMs of histones may either directly affect chromatin compaction and assembly or serve as binding sites for effector proteins, including other chromatin-modifying or chromatin-remodeling complexes, and ultimately influence transcription initiation and/or elongation.
Most, if not all, histone PTMs are reversible. Many enzymes that are involved in their addition and removal have been identified. These include histone acetyltransferases (HATs; also known as lysine acetyltransferases) and histone deacetylases (HDACs; also known as lysine deacetylases); lysine methyltransferases (KMTs) and lysine demethylases (KDMs); and ubiquitylation enzymes (that is, E1, E2 and E3 enzymes) and deubiquitylases (DUBs). These enzymes often exist in multisubunit complexes and modify specific residues either on the amino-terminal tails or within the globular domains of core histones (H2A, H2B, H3 and H4). For example, in the two repressive Polycomb group (PcG) protein complexes, Polycomb repressive complex 1 (PRC1) contains either ring finger protein 1A (RING1A) or RING1B, both of which catalyze the monoubiquitylation of histone H2A at lysine 119 (H2AK119ub1), and PRC2 contains enhancer of zeste 2 (EZH2), which catalyzes the trimethylation of H3K27 (H3K27me3). Additionally, some Trithorax group protein complexes contain the mixed-lineage leukemia (MLL) family of KMTs that catalyze the formation of the transcriptionally activating H3K4me3 mark. Beyond PTMs of histones, chromatin compaction is also affected by ATP-dependent chromatin-remodeling complexes that use energy from ATP hydrolysis to exchange histones and to reposition or evict nucleosomes. Approximately 30 genes that encode the ATPase subunits have been identified in mammals. On the basis of the sequence and the structure of these ATPases, chromatin-remodelling complexes are divided into four main families: SWI/SNF, ISWI, chromodomain-helicase DNA-binding protein (CHD) and INO80 complexes.
Many histone modifiers and chromatin remodelers have been implicated in stem cell pluripotency, cellular differentiation and development.
1. http://sci-hub.tw/https://www.nature.com/articles/nrg3607
Nearly all cells of an organism share the same genome but show different phenotypes and carry out diverse functions. Individual cell types, which are characterized by distinct gene expression patterns, are generated during development and are then stably maintained. The chromatin state — the packaging of DNA with both histone and non-histone proteins — has marked effects on gene expression and is believed to contribute to the establishment and the maintenance of cell identities. Indeed, developmental transitions are accompanied by dynamic changes in chromatin states. The assembly and the compaction of chromatin are regulated by multiple mechanisms, including DNA modifications (for example, cytosine methylation and cytosine hydroxymethylation), post-translational modifications (PTMs) of histones (for example, phosphorylation, acetylation, methylation and ubiquitylation), the incorporation of histone variants (for example, H2A.Z and H3.3), ATP-dependent chromatin remodelling and non-coding RNA (ncRNA)-mediated pathways. In recent years, substantial progress has been made in understanding the roles of histone modifications and chromatin remodeling in cellular differentiation. PTMs of histones may either directly affect chromatin compaction and assembly or serve as binding sites for effector proteins, including other chromatin-modifying or chromatin-remodeling complexes, and ultimately influence transcription initiation and/or elongation.
Most, if not all, histone PTMs are reversible. Many enzymes that are involved in their addition and removal have been identified. These include histone acetyltransferases (HATs; also known as lysine acetyltransferases) and histone deacetylases (HDACs; also known as lysine deacetylases); lysine methyltransferases (KMTs) and lysine demethylases (KDMs); and ubiquitylation enzymes (that is, E1, E2 and E3 enzymes) and deubiquitylases (DUBs). These enzymes often exist in multisubunit complexes and modify specific residues either on the amino-terminal tails or within the globular domains of core histones (H2A, H2B, H3 and H4). For example, in the two repressive Polycomb group (PcG) protein complexes, Polycomb repressive complex 1 (PRC1) contains either ring finger protein 1A (RING1A) or RING1B, both of which catalyze the monoubiquitylation of histone H2A at lysine 119 (H2AK119ub1), and PRC2 contains enhancer of zeste 2 (EZH2), which catalyzes the trimethylation of H3K27 (H3K27me3). Additionally, some Trithorax group protein complexes contain the mixed-lineage leukemia (MLL) family of KMTs that catalyze the formation of the transcriptionally activating H3K4me3 mark. Beyond PTMs of histones, chromatin compaction is also affected by ATP-dependent chromatin-remodeling complexes that use energy from ATP hydrolysis to exchange histones and to reposition or evict nucleosomes. Approximately 30 genes that encode the ATPase subunits have been identified in mammals. On the basis of the sequence and the structure of these ATPases, chromatin-remodelling complexes are divided into four main families: SWI/SNF, ISWI, chromodomain-helicase DNA-binding protein (CHD) and INO80 complexes.
Many histone modifiers and chromatin remodelers have been implicated in stem cell pluripotency, cellular differentiation and development.
1. http://sci-hub.tw/https://www.nature.com/articles/nrg3607
