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Biology subjects

O'Connor, B. P.

Publications and source records attributed to O'Connor, B. P..

2 recordsLinked to original sources

GATA2 regulates mast cell identity and responsiveness to antigenic stimulation by promoting chromatin remodeling at super-enhancers

Mast cells (MCs) are critical effectors of allergic inflammation and protection against parasitic infections. We previously demonstrated that transcription factors GATA2 and MITF are the MC lineage-determining factors (LDTFs). However, it is unclear whether these LDTFs regulate chromatin accessibility at MC enhancer regions. In this study, we demonstrate that GATA2 promotes chromatin accessibility at the super-enhancers of MC identity genes and primes both typical and super-enhancers at genes that respond to antigenic stimulation. We found that the number and densities of GATA2-but not MITF-bound sites at the super-enhancers were several folds higher than that at the typical enhancers. Our studies revealed that GATA2 promotes robust gene transcription to maintain MC identity and respond to antigenic stimulation by binding to super-enhancer regions with dense GATA2 binding sites available at key MC genes.

molecular biology↗

SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness

Alternative splicing (AS) of pre-mRNA is a critical component of transcriptional regulation that diversifies the cellular proteome. The Serine-Arginine Protein Kinases (SRPK) initiate early events in AS. Using conditional knockout mice (cKO), we demonstrated the importance of the X-linked gene Srpk3 in B lymphocyte development and in response to immunization in vivo. Significantly decreased numbers of immature and mature B cells were observed in Srpk3-cKO BM relative to wild-type (WT). Immunization of Srpk3-cKO mice with a T lymphocyte-independent type-2 antigen elicited greatly reduced amounts of specific IgG3. Srpk3 deletion resulted in hundreds of differentially spliced mRNAs in B cells, including mRNAs encoding proteins associated with signaling pathways and mitochondrial function. Several alternative splicing outcomes in Srpk3-cKO cells are due to altered splicing regulation of SR proteins. We conclude that Srpk3 is an immunomodulatory kinase that controls humoral immunity via its regulation of pre-mRNA splicing, antibody production, and metabolism in B cells.\n\nOne Sentence SummarySRPK3 regulates alternative splicing of pre-mRNA that is crucial for B cell development, activation and antibody responses.

immunology↗