Biology subjects

Fraszczak, J.

Publications and source records attributed to Fraszczak, J..

3 recordsLinked to original sources

bioRxiv2026

GFI1 as a novel regulator of γδ T cell development and the IL-17/IFNγ lineage commitment

GFI1 is a DNA-binding zinc finger transcription factor regulating the commitment of hematopoietic precursors to myeloid and lymphoid lineages. Here we report that GFI1 is expressed in {gamma}{delta} T cells and restricts the cellularity of ROR{gamma}t+V{gamma}6+ {gamma}{delta}T cells that produce high levels of IL-17A, while promoting the expansion of V{gamma}1+ and V{gamma}4+ {gamma}{delta}T cells. Absence of GFI1 results in a pronounced bias toward the production of {gamma}{delta}T17 cells, commencing post-birth. Additionally, we observe an expansion of ROR{gamma}t+/MAF+ cells within the thymic DN1e population of GFI1-deficient mice. The DN1e population, along with other DN subsets in GFI1 knock-out (KO) mice, exhibits a distinctive {gamma}{delta}T17 cell-specific transcriptomic profile. Specifically, DN1, DN3, and {gamma}{delta} T cells lacking GFI1 show upregulation of the B-ZIP transcription factor MAF, which regulates genes critical for {gamma}{delta}T cells, such as Il17a, Il22, and Blk that are all induced in Gfi1 deficient cells. The Maf gene is occupied by GFI1 in DN pre-T cells at cognate binding sites in its promoter region, suggesting that GFI1 acts as a direct repressor of Maf. We conclude that GFI1 functions as a novel regulator of V{gamma}6+ {gamma}{delta}T17 precursor cells restricting their peripheral expansion by acting upstream of a MAF dependent regulatory network. Highlights- GFI1 controls the expansion of {gamma}{delta} T cells in peripheral lymphoid organs and in barrier tissues. - GFI1 specifically restricts expansion of {gamma}{delta} T cells secreting IL-17 by acting upstream of a MAF dependent transcriptional regulatory network. - GFI1 plays a cell intrinsic role in controlling the generation of {gamma}{delta}T cells through the repression of Maf. - GFI1 controls a MAF+/ROR{gamma}t+ {gamma}{delta}T cell precursor cell population within the DN1e cell subset.

immunology↗

bioRxiv2023

A conserved role of hnRNPL in regulating alternative splicing of transcriptional regulators necessary for B cell activation

The multifunctional RNA-binding protein hnRNPL has been implicated in antibody class switching but its broader function in B cells is unknown. Here, we show that hnRNPL is essential for B cell activation, and thereby germinal center and antibody responses. Upon activation, hnRNPL-deficient B cells show proliferation defects and increased apoptosis. Comparative analysis of RNA-seq data from activated B cells and another 8 hnRNPL-depleted cell types reveals a common function in the MYC and E2F transcriptional programs required for proliferation, likely borne out of alternative splicing changes affecting multiple transcription regulators. Notably, while individual gene expression changes were cell type specific, several alternative splicing events affecting histone modifiers like, KDM6A, NSD2, and SIRT1, were conserved across cell types, which could contribute to gene expression changes and other phenotypes upon hnRNPL loss. In line with reduced SIRT1, hnRNPL-deficient B cells had dysfunctional mitochondria and ROS overproduction, which could contribute to defects in B cell activation. Thus, hnRNPL is essential for the resting-to-activated B cell transition by regulating transcriptional programs and metabolism, most likely through the alternative splicing of several histone modifiers.

immunology↗

bioRxiv2021

GFI1 tethers the NuRD complex to open and transcriptionally active chromatin in myeloid progenitors

GFI1 is a SNAG-domain, DNA binding transcriptional repressor which controls myeloid differentiation, in particular the formation of neutrophils. Here we show that GFI1 interacts with the chromodomain helicase CHD4 and other components of the "Nucleosome remodeling and deacetylase" (NuRD) complex. In granulo-monocytic precursors, GFI1, CHD4 or GFI1/CHD4 complexes occupy sites of open chromatin enriched for histone marks associated with active transcription suggesting that GFI1 recruits the NuRD complex to target genes that are regulated by active or bivalent promoters and active enhancers. Our data also show that GFI1 and GFI1/CHD4 complexes occupy promoters of different sets of genes that are either enriched for IRF1 or SPI-1 consensus sites, respectively. During neutrophil differentiation, overall chromatin closure and depletion of H3K4me2 occurs at different degrees depending on whether GFI1, CHD4 or both are present, indicating that GFI1 affects the chromatin remodeling activity of the NuRD complex. Moreover, GFI1/CHD4 complexes regulate chromatin openness and histone modifications differentially to enable regulation of target genes affecting the signaling pathways of the immune response or nucleosome organization or cellular metabolic processes.

molecular biology↗