Figure 1: Model of molecular synergy implicated by genetic determinants (asterisks) that share clinical features of CHARGE syndrome.
From: Genetic analysis of CHARGE syndrome identifies overlapping molecular biology
Cis-regulatory retinoic acid response elements (red DNA; RAREs) control cell-specific transcription of retinoic acid (RA) responsive genes, like FGF8 (orange DNA). (a) In the absence of RA, polycomb repressive complex 2 (PRC2) and KMT2D are recruited to RAREs, where they catalyze H3K27Me3 and H3K4Me1 respectively, promoting FGF8 transcriptional repression. (b) In response to RA, the RERE/NR2F2/P300 complex forms, binding nuclear heterodimers of retinoic acid receptors (RAR/RXR) at RAREs. Histone acetyltransferase P300 and KMT2D cooperate to activate enhancer and enhancer–promoter looping that requires nucleosome translocation along the DNA by CHD7. KDM6A demethylates the repressive H3K27Me3 histone modifications. Enhancer–promoter looping is stabilized by the mediator complex (gray oval). CHD7 translocates nucleosomes to permit transcription of FGF8 by RNA pol II. PUF60 helps form the transcription bubble required for RNA Pol II transcription and pre–messenger RNA splicing.
