Control of gene expression and assembly of chromosomal subdomains by chromatin regulators with antagonistic functions

Abstract

Epigenetic regulation of higher-order chromatin structure controls gene expression and the assembly of chromosomal domains during cell division, differentiation, and development. The proposed "histone code" integrates a complex system of histone modifications and chromosomal proteins that establish and maintain distinctive types of chromatin, such as euchromatin, heterochromatin, and centromeric (CEN) chromatin. The reversible nature of histone acetylation, phosphorylation, and (most recently discovered) methylation are mechanisms for controlling gene expression and partitioning the genome into functional domains. Many different regions of the genome contain similar epigenetic marks (histone modifications), raising the question as to how they are independently specified and regulated. In this review, we will focus on several recent discoveries in chromatin and chromosome biology: (1) identification of long-elusive histone "de-methylating" enzymes that affect chromatin structure, and (2) assembly and maintenance of chromatin domains, specifically heterochromatin and euchromatin, through a dynamic equilibrium of modifying enzymes, histone modifications, and histone variants identified biochemically and genetically.

Genome-wide prediction of conserved and nonconserved enhancers by histone acetylation patterns

“…Many epigenetic modifications are known to occur in active and repressed chromatin regions (for review, see Jenuwein and Allis 2001;Felsenfeld and Groudine 2003;Peterson and Laniel 2004;Lam et al 2005;Margueron et al 2005;Martin and Zhang 2005), and many of these modifications are known to occur at important regulatory elements, e.g., the high levels of histone acetylation that are found at gene promoters and at many enhancers. Some of these modifications are known to be associated with active chromatin, including acetylation of histone H3 on lysines 9 and 14 and methylation on lysines 4, 36, and 79, while other modifications, including methylation of histone H3 on lysines 9 and 27, are linked with repressive chromatin environments, although recent data have shown an overlap of active and repressive modifications in distinct chromatin subpopulations (Bernstein et al 2006;Roh et al 2006).…”

Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves γ-globin activation by CREB1 and ATF-2

“…10 Mechanistically, both agents bind a central zinc atom in HDAC to produce hyperacetylation of histone H3 (H3) and H4 28,29 to activate gene transcription. 30,31 We previously proposed a dual mechanism for ␥-globin gene activation by HDACIs involving (1) hyperacetylation of histone tails to produce open chromatin configurations and (2) transcription factor binding. 16 We expanded our investigations to identify the effector molecules involved in ␥-globin trans-activation by NaB and TSA via p38 MAPK signaling.…”

Maps of cis-Regulatory Nodes in Megabase Long Genome Segments are an Inevitable Intermediate Step Toward Whole Genome Functional Mapping

“…These modifications form an epigenetic pattern along the genome, or "histone code" [80], and provide binding sites for specific proteins that in turn induce alterations in chromatin structure and gene expression. Acetylation of lysine residues in histones is generally linked with open chromatin and active transcription, whereas methylation of lysine and arginine residues of histones is associated with either chromatin activation or silencing depending on methylation sites [81].…”