ARID1a Associates with Lymphoid-Restricted Transcription Factors and Has an Essential Role in T Cell Development

Abstract

Maturation of lymphoid cells is controlled by the action of stage and lineage-restricted transcription factors working in concert with the general transcription and chromatin remodeling machinery to regulate gene expression. To better understand this functional interplay, we used Biotin Identification in human embryonic kidney cells to identify proximity interaction partners for GATA3, TCF7 (TCF1), SPI1, HLF, IKZF1, PAX5, ID1, and ID2. The proximity interaction partners shared among the lineagerestricted transcription factors included ARID1a, a BRG1-associated factor complex component. CUT&RUN analysis revealed that ARID1a shared binding with TCF7 and GATA3 at a substantial number of putative regulatory elements in mouse T cell progenitors. In support of an important function for ARID1a in lymphocyte development, deletion of Arid1a in early lymphoid progenitors in mice resulted in a pronounced developmental arrest in early T cell development with a reduction of CD4 + CD8 + cells and a 20-fold reduction in thymic cellularity. Exploring gene expression patterns in DN3 cells from Wt and Arid1a-deficient mice suggested that the developmental block resided in the DN3a to DN3b transition, indicating a deficiency in b-selection. Our work highlights the critical importance of functional interactions between stage and lineage-restricted factors and the basic transcription machinery during lymphocyte differentiation.

GATA-3 is a proto-oncogene in T-cell lymphoproliferative neoplasms

“…Like other transcription factors, GATA-3 is a challenging therapeutic target, thus we sought to characterize its interactome by BioID. Our findings are generally consistent with the interactome previously identified in normal T cells [62], including the observation that transcriptional co-activators and corepressors, many of which are subject to recurrent gains and losses in T-cell neoplasms, respectively, were identified. However, we were most intrigued by p300, as post-translational acetylation of many GATA family members has been variously associated with regulating protein stability, protein-protein interactions, and DNA binding affinity [52,63], and previous studies further suggest a regulatory role for post-translational acetylation in regulating GATA-3 function [56].…”

ARID1A Is a Prognostic Biomarker and Associated with Immune Infiltrates in Hepatocellular Carcinoma

“…Some studies suggest that ARID1A have an essential function role in the formation of lymphocytes. In animal studies, it is found that the absence of ARID1A in early lymphoid progenitor cells of mice leads to the obvious stagnation of early T cell development [ 32 ]. Our findings further indicate that the ARID1A expression is significantly linked to T helper cells.…”

ARID1A Downregulation Predicts High PD-L1 Expression and Worse Clinical Outcome in Patients With Gallbladder Cancer

“…Notably, recent studies revealed the vital effect of ARID1A on tumor immunity. One study confirmed that ARID1A plays an important role in lymphocyte development, whereas ARID1A deletion can lead to a developmental arrest in early T cells (28). Loss of ARID1A was found to have a significant correlation with the expression of IFN-g and checkpoint genes (including PD-L1, CTLA4, and PDCD1) in microsatellite-stable colorectal cancer (29).…”