Intrinsic Disorder of the BAF Complex: Roles in Chromatin Remodeling and Disease Development

Abstract

The two-meter-long DNA is compressed into chromatin in the nucleus of every cell, which serves as a significant barrier to transcription. Therefore, for processes such as replication and transcription to occur, the highly compacted chromatin must be relaxed, and the processes required for chromatin reorganization for the aim of replication or transcription are controlled by ATP-dependent nucleosome remodelers. One of the most highly studied remodelers of this kind is the BRG1- or BRM-associated factor complex (BAF complex, also known as SWItch/sucrose non-fermentable (SWI/SNF) complex), which is crucial for the regulation of gene expression and differentiation in eukaryotes. Chromatin remodeling complex BAF is characterized by a highly polymorphic structure, containing from four to 17 subunits encoded by 29 genes. The aim of this paper is to provide an overview of the role of BAF complex in chromatin remodeling and also to use literature mining and a set of computational and bioinformatics tools to analyze structural properties, intrinsic disorder predisposition, and functionalities of its subunits, along with the description of the relations of different BAF complex subunits to the pathogenesis of various human diseases.

Characterization of functional disordered regions within chromatin-associated proteins

“…Various experiments allow for investigation of structural properties, including the identification of transient secondary structure and assessment of the magnitude and timescale of conformational dynamics ( Gibbs et al., 2017 ; Jensen et al., 2014 ). In addition, the effects of PTMs and mechanisms of binding can straightforwardly be studied ( Theillet et al., 2012 ).…”

“…IDRs are also abundant in histone chaperones, transcription factors, chromatin remodeling proteins, chromatin modifying proteins, and architectural proteins (Tantos et al, 2011;Sandhu, 2009;Lazar et al, 2016;Hadidy and Uversky, 2019). The IDRs are now being recognized to play a much more direct role in chromatin regulation than simply dynamically linking folded functional domains.…”

Emerging trends in chromatin remodeler plasticity in mesenchymal stromal cell function

“…[94][95][96] Lineage differentiation by regulating expression of Nanog reveals specialized role of BAF complex subunits Brg1, Baf57, and Baf47. 97,98 Recent studies indicate that BAF complex has also emerged as an important regulator of MSC tri-lineage differentiation by interaction with tissue-specific transcription factors and crosstalk with cell signaling machinery. 24,98,99 Bone morphogenetic protein-2 (BMP-2) treatment of premyogenic cells C2C12, leads to an induction of various subunits of the SWI/SNF complex along with an induction of early responsive osteogenic gene alkaline phosphatase (Alpl).…”

“…SWI/SNF (Brahma‐Associated Factor, BAF) plasticity associated with combinatorial subunit assembly was initially reported in the context of neural cell development and heterochromatin formation in ES cell differentiation 94‐96 . Lineage differentiation by regulating expression of Nanog reveals specialized role of BAF complex subunits Brg1, Baf57, and Baf47 97,98 . Recent studies indicate that BAF complex has also emerged as an important regulator of MSC tri‐lineage differentiation by interaction with tissue‐specific transcription factors and crosstalk with cell signaling machinery 24,98,99 .…”

Structure and DNA binding analysis of AT‐rich interaction domain present in human BAF‐B specific subunit BAF250b

“…A 2,236 residues long DNA binding protein BAF250b (also known as ARID1b) is the largest core subunit of the BAF‐B class of SWI/SNF chromatin remodeling complexes 1–3 . BAF250b and its paralog BAF250a (also known as ARID1a) are mutually exclusive in the BAF complexes and are more than 57% identical across their entire length 2,4–8 .…”