IL-10 transcription is negatively regulated by BAF180, a component of the SWI/SNF chromatin remodeling enzyme

Abstract

BackgroundSWI/SNF chromatin remodeling enzymes play a critical role in the development of T helper lymphocytes, including Th2 cells, and directly program chromatin structure at Th2 cytokine genes. Different versions of SWI/SNF complexes, including BAF and PBAF, have been described based on unique subunit composition. However, the relative role of BAF and PBAF in Th cell function and cytokine expression has not been reported.ResultsHere we examine the role of the PBAF SWI/SNF complex in Th cell development and gene expression using mice deficient for a PBAF-specific component, BAF180. We find that T cell development in the thymus and lymphoid periphery is largely normal when the BAF180 gene is deleted late in thymic development. However, BAF180-deficient Th2 cells express high levels of the immunoregulatory cytokine IL-10. BAF180 binds directly to regulatory elements in the Il-10 locus but is replaced by BAF250 BAF complexes in the absence of BAF180, resulting in increased histone acetylation and CBP recruitment to the IL-10 locus.ConclusionsThese results demonstrate that BAF180 is a repressor of IL-10 transcription in Th2 cells and suggest that the differential recruitment of different SWI/SNF subtypes can have direct consequences on chromatin structure and gene transcription.

The roles of chromatin-remodelers and epigenetic modifiers in kidney cancer

“…It was later discovered that PBRM1-deficient mice more likely have a failure in coronary vessel development [35]. Deletion of PBRM1 in mouse T cells enhanced Th2 differentiation and significantly elevated IL-10 expression [36]. PBRM1 is mutated in some human breast cancers, and its re-expression inhibits cell proliferation and induces p21 expression [37].…”

“…Furthermore, PBRM1 and BRD7 are found to be critical for p53 to induce replicative senescence [38]. Interestingly, genes that are regulated by PBRM1 are highly dependent on the cell state, as its repression targets are very different in resting and stimulated Th2 cells [36]. PBRM1 was also found to be required for retinoic acid-dependent gene activation [34].…”

Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes

“…ARID1A is the most commonly mutated SWI/SNF subunit in cancer, due to transcriptional functions that are non-redundant with ARID1B (21,22); however, cancers with deletions in ARID1A are dependent on ARID1B for viability (23) due to redundant, essential functions at enhancers (22). Additionally, homologous complexes can display transcriptionally antagonistic roles, as has been observed for ARID1A and ARID2-containing complexes at specific gene targets (8,20,24). Targeting specific SWI/SNF complexes has been proposed both for alleviating subunit-specific pathogenic function as well as to target essential redundant functions in cancers with mutations in the genes for specific subunits (25,26).…”

The BAH domain of BAF180 is required for PCNA ubiquitination

“…The BAH domains are not assembled into the PBAF complex in the absence of the C-terminus PBAF (or SWI/SNF-B) complex is one of the SWI/SNF families of chromatin remodeling complexes and has been implicated in the DNA damage response, in addition to its known roles in transcriptional regulation [34][35][36][37]. The PBAF complex shares a large set of subunits with the BAF (or SWI/SNF-A) complex, apart from three PBAF-specific components, BAF180, BRG7 and BAF200.…”