title: Heterochromatin as an incubator for pathology and treatment non-response: implication for neuropsychiatric illness.
abstract: Heterochromatin is a higher order assembly that is characterized by a genome-wide distribution, gene-repression, durability and potential to spread. In this light, it is an appealing mechanism to interpret the neurobiology of complex brain disorders such as schizophrenia where downregulation of expression appears to be the norm. H3K9 methylation (H3K9me) can initiate the seeding of a heterochromatin assembly on an inactive or poorly coordinated promoter as a consequence of a decline in transactivators either from disuse or from misuse. H3K9me can extend its influence by spatial spreading through the mechanism of recursively recruiting adapters, such as heterochromatin protein 1 (HP1) homodimers. HP1 itself serves as a platform for other repressive proteins such as DNA methyltransferases. In full color, heterochromatin can occupy genome-wide gene networks, tissue specific ontologies and even rearrange the nuclear architecture. Heterochromatin in the brain is modified by small molecule pharmacology and serves a physiological role in the functioning of dopamine neurons and the construction of memory. From a therapeutic perspective, the durable nature of heterochromatin implies that it may require disassembly before the full genomic-potential of standard pharmacotherapies is achieved, especially in treatment resistant patients.
authors.affiliation: The Psychiatric Institute, University of Illinois at Chicago, Chicago, IL 60612, USA. rsharma@psych.uic.edu
authors.forename: R P
authors.initials: RP
authors.lastname: Sharma
authors.forename: D P
authors.initials: DP
authors.lastname: Gavin
authors.forename: K A
authors.initials: KA
authors.lastname: Chase
mesh_terms: D000107:Acetylation; D042002:Chromatin Assembly and Disassembly; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006570:Heterochromatin / Q000235:genetics*; D006649:Histocompatibility Antigens / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D012559:Schizophrenia / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D006649:Histocompatibility Antigens; D006657:Histones; D000090266:Chromobox Protein Homolog 5; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase