Structure of nucleosome-bound human PBAF complex

Abstract

BAF and PBAF are mammalian SWI/SNF family chromatin remodeling complexes that possess multiple histone/DNA-binding subunits and create nucleosome-depleted/free regions for transcription activation. Despite previous structural studies and recent advance of SWI/SNF family complexes, it remains incompletely understood how PBAF-nucleosome complex is organized. Here we determined structure of 13-subunit human PBAF in complex with acetylated nucleosome in ADP-BeF3-bound state. Four PBAF-specific subunits work together with nine BAF/PBAF-shared subunits to generate PBAF-specific modular organization, distinct from that of BAF at various regions. PBAF-nucleosome structure reveals six histone-binding domains and four DNA-binding domains/modules, the majority of which directly bind histone/DNA. This multivalent nucleosome-binding pattern, not observed in previous studies, suggests that PBAF may integrate comprehensive chromatin information to target genomic loci for function. Our study reveals molecular organization of subunits and histone/DNA-binding domains/modules in PBAF-nucleosome complex and provides structural insights into PBAF-mediated nucleosome association complimentary to the recently reported PBAF-nucleosome structure.

Endothelial Arid1a deletion disrupts the balance among angiogenesis, neurogenesis and gliogenesis in the developing brain

“…Histone modification of endothelial cells can reveal information about the regulatory mechanisms of changes in gene expression. Arid1a has been associated with nucleosome composition, histone modification and fate determination 27,34,35 . We examined a range of histone modifications, including H3K4me3, H3K9me3, H3K27me3, H3K27ac, and H3k36me3, where H3K27ac was significantly increased in Arid1a ‐deficient endothelial cells (Figure 5A,B).…”

GNE-235: A Lead Compound Selective for the Second Bromodomain of PBRM1

“…A trace of contaminating SPhos oxide remained that could be removed by rechromatographing and eluting with a shallow gradient of methanol in DCM, yielding apparently pure fractions among those eluting later. 1 (R)-6-(Furan-2-yl)-4-(2-methylpiperidin-1-yl)pyridazin-3-amine (30). The R-enantiomer was synthesized from 39 in the manner described above for 29, although the coupling reaction did not proceed to completion after 18 h. After workup and chromatography, the desired product was obtained in ∼10% yield (12.2 mg, 0.047 mmol).…”

BCL7 proteins, metazoan-specific subunits of the mammalian SWI/SNF complex, bind the nucleosome core particle

“…Interestingly, although mSWI/SNF is an NCP-displacing multi protein complex, until recently only SMARCB1 and the ATPase BRG1 25,26 , had been reported as proteins carrying clearly mapped NCP-binding domains. The interaction of PBAF with the nucleosome has been further clarified with the identification of more subunits coming in contact with the nucleosome 19 , but much remains to be discovered about the interactions between mSWI/SNF and its substrate.…”

“…Despite this, the structure, the molecular details of interaction and the function of BCL7 subunits within mSWI/SNF are poorly defined at best. The topological information currently available is limited to the observation that BCL7 proteins make contacts with BRG1, SMARCB1, DPF2, actin and histone H2B 18,19 . Recent studies have reported the cryo-EM structure of the SWI/SNF complex.…”

“…Recent studies have reported the cryo-EM structure of the SWI/SNF complex. Unfortunately, they do not inform us on BCL7 proteins: two studies concerned the yeast SWI/SNF complex and BCL7 are absent in this species 20,21 ; in studies of reconstituted mSWI/SNF, BCL7 proteins were either omitted 22,23 or not detectable 19 ; and studies with the endogenous human complex had overall poor resolution and does not provide molecular details on BCL7 proteins 24 .…”