KMT2C/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies

Abstract

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.

Keywords: CBP; COMPASS complex; Demethylase; EHMT1; EP300; Epigenetics; Histone deacetylase; KDM6A; KMT2C; KMT2D; Kabuki syndrome; Kleefstra syndrome; Lysine methyltransferase; Rubinstein-Taybi syndrome.

Fig. 1

a Histone-modifying genes of interest (KMT2C, KMT2D, EHMT1, KDM6A, CRBBP, and EP300) functional domains scale schematic. Amino acids (aa), Plant homeodomain (PHD), high mobility group domain (HMG), F/Y-rich N-terminus domain (FYRN), F/Y-rich C-terminus domain (FYRC), SET domain (SET), post-SET domain (POST), pre-SET domain (PRE), Ankyrin repeat domain (ANK), JmjC domain (JmjC), tetratricopeptide repeat protein domain (TPR), transcriptional adapter zinc binding domain (TAZ), kinase-inducible domain interacting domain (KIX), bromodomain (BROMO), histone acetyltransferase domain (HAT). b Schematic of K_CDCOM. COMPASS-like complexes (K_CDCOMs, also historically known as ASC2-binding complexes, ASCOMs) bind multiple unique subunits (NCOA6/ASC2, KDM6A/UTX, PTIP, and PAGR1/PA1) and interact with chromatin via histone tail post-translational modifications and DNA binding cofactors. RA retinoic acid. WRAD WDR5 (WD repeat domain 5), RBBP5 (retinoblastoma binding protein 5), ASHL2 (absent, small or homeotic 2-like), and DPY-30 (Dumpy-30)

Fig. 2

Craniofacial phenotype of K_CDCOM-associated diseases. Representative facial and profile photographs of patients with indicated diseases and mutations

Fig. 3

Epigenetic craniofacial enhancer analysis. Epigenetic analysis of conserved craniofacial enhancer element hs1431 shown as Genome Browser tracks of aligned indicated ChIP Seq signal peaks. Y-axis indicates coverage by estimated fragments normalized to millions of reads mapped generated from next generation sequencing. Experiments are from mouse 4 days old embryoid bodies (MLL3^−/−;MLL4^flox/flox) [48] and e11.5 embryonic mouse facial tissu e[128]. Data analyzed are publically available from Gene Expression Omnibus database (accession numbers GSE50534 and GSE49413). Data analysis, peak calling, and visualization were performed in BioWardrobe [130] with GRCm38/mm10 genome build