Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin

Abstract

Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2). Using exome sequencing, we discovered missense mutations in AFF4, a core component of the SEC in three unrelated probands with a novel syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS), that we have named CHOPS syndrome (C for Cognitive impairment and Coarse facies, H for Heart defects, O for Obesity, P for Pulmonary involvement and S for Short stature and Skeletal dysplasia). Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 between CdLS and CHOPS syndrome. Direct molecular interaction between SEC, cohesin and RNAP2 was demonstrated. This data supports a common molecular pathogenesis for CHOPS syndrome and CdLS caused by disturbance of transcriptional elongation due to alterations in genome-wide binding of AFF4 and cohesin.

TBP loading by AF4 through SL1 is the major rate-limiting step in MLL fusion-dependent transcription

“…15,16 SIAH proteins are ubiquitin ligases that promote proteasome-dependent degradation. Multiple germline mutations in this motif of AF5Q31 were found in patients with CHOPS syndrome, 17 who exhibit developmental defects similar to those of Cornelia de Lange syndrome. The mutations appear to be gain-of-function mutations as the mutant proteins are resistant to the SIAHdependent degradation.…”

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

“…CHOPS syndrome is caused by gain-of-function mutations in AFF4 , which encodes a key component of the SEC ( fig. 6 b) [Izumi et al, 2015].…”

“…5 c) [Ball et al, 2014;Izumi et al, 2015]. The first suggests that the cohesin complex facilitates gene promoter-enhancer interactions, whereas the second indicates a direct role in transcriptional regulation by interacting with RNAP2.…”

“…By using its ring structure, cohesin is known to promote DNA looping, allowing physical interactions between distal regulatory elements and promoter regions [Ball et al., 2014]. A direct transcriptional regulatory role of cohesin is supported by the observation that RNAP2, as well as the SEC, interacts with cohesin, specifically STAG1-cohesin [Izumi et al, 2015]. Furthermore, cohesin-binding sites were enriched within the promoter regions of CdLS dysregulated genes, suggesting its role in transcriptional initiation or elongation control .…”

“…6 a) [Izumi et al, 2015]. CHOPS syndrome probands were originally suspected to have CdLS, although they lacked several typical features of CdLS, such as microcephaly.…”