期刊
CLINICAL EPIGENETICS
卷 12, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13148-019-0802-2
关键词
COMPASS complex; Epigenetics; Kabuki syndrome; Rubinstein-Taybi syndrome; Kleefstra syndrome; Lysine methyltransferase; Demethylase; Histone deacetylase; KMT2D; KMT2C; KDM6A; EP300; CBP; EHMT1
资金
- Center for Pediatrics Genomics, Cincinnati Research Foundation
- T32 training grant [NIH NIAID 5T32AI060515-15]
The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.
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