Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes

Abstract

Some genetic disorders caused by mutations in genes encoding components of the transcriptional machinery as well as proteins involved in epigenetic modification of the genome share many overlapping features, such as facial dysmorphisms, growth problems and developmental delay/intellectual disability. As a basis for some shared phenotypic characteristics in these syndromes, a similar transcriptome disturbance, characterized by global transcriptional dysregulation, is believed to play a major role. In this review article, a general overview of gene transcription is provided, and the current knowledge of the mechanisms underlying some disorders of transcriptional regulation, such as Rubinstein- Taybi, Coffin-Siris, Cornelia de Lange, and CHOPS syndromes, are discussed.

Keywords: Chromatin remodeling; Malformation syndromes; Transcriptional regulation.

Fig. 1

Schematic illustration of histone modification and chromatin remodeling. TF = DNA-binding transcription factor.

Fig. 2

Schematic illustration of gene transcription. GTF = General transcription factor complexes.

Fig. 3

a Patient with RSTS. Note downslanted palpebral fissures, broad thumb and hallux. b Causative genes for RSTS encode the CREB-binding protein and p300 responsible for histone acetylation.

Fig. 4

a Schematic illustration of the BAF complex, mutated in CSS. The BAF complex components whose mutations were found in CSS and NCBRS are indicated by red characters. b The BAF complex is responsible for chromatin remodeling.

Fig. 5

a Patient with CdLS. Note arched eyebrow and long philtrum. b Schematic illustration of the cohesin complex. c The Cohesin complex promotes enhancer-promoter interaction and controls gene transcription via interacting with RNAP2. Ac = Acetylation site of the SMC3 protein.

Fig. 6

a Patients with CHOPS syndrome. Note round faces and arched eyebrows. b Schematic illustration of SEC. c Disease mechanism of CHOPS syndrome. SEC is responsible for transcriptional elongation. In the CHOPS syndrome, accumulation of SEC causes transcriptional overactivation by excessive transcriptional elongation.