Biology subjects

Pease, N.

Publications and source records attributed to Pease, N..

3 recordsLinked to original sources

bioRxiv2026

Sequential and coordinated control of human plasma cell differentiation by IRF4 and BLIMP1 utilizing a discriminating ISRE/EICE motif lexicon

The transcription factors IRF4 and BLIMP1 (PRDM1) promote plasma cell (PC) differentiation by repressing B cell identity genes while inducing the unfolded protein response, ER/Golgi biogenesis, and immunoglobulin secretion. How IRF4 and BLIMP1 partition and coordinate their genomic activities during plasma cell differentiation remains unresolved. Using naive human B cells and a stepwise in vitro differentiation system, we performed CRISPR/Cas9 perturbations of IRF4 or PRDM1 in plasma cell precursors followed by single-cell RNA sequencing. Despite their mutually reinforced expression and shared recognition of related IRF-family motifs (ISREs and EICEs), loss of IRF4, but not of BLIMP1, yielded a stunted intermediate with incomplete silencing of B cell identity genes and defective induction of the secretory program. Multiome profiling, base-pair-resolution motif modeling, CUT&RUN, and DNA-binding assays identified non-conserved nucleotides within ISRE/EICE motifs that discriminate IRF4 from BLIMP1 binding. These findings reveal a motif-lexicon-dependent IRF4-BLIMP1 interplay, in which IRF4 first acts independently and then in concert with BLIMP1. This regulatory logic may also underlie programming of additional lymphocyte effector states.

immunology↗

bioRxiv2024

A timed epigenetic switch balances T and ILC lineage proportions in the thymus

How stem and progenitor cells give rise to multiple cell types in defined numbers and proportions is a central question in developmental biology. Epigenetic switches, acting at single gene loci, can generate extended delays in the activation timing of lineage-specifying genes, and thereby impact lineage decisions and cell type output of progenitors. Here, we analyzed a timed epigenetic switch controlling Bcl11b, a transcription factor that drives T cell lineage commitment, but only after a long multi-day time delay in expression. To investigate roles for this delay in controlling lineage decision making, we analyzed progenitors with a deletion in a distal Bcl11b enhancer, that further extends this delay by [~]3 days. Strikingly, delaying Bcl11b activation reduces T cell output but enhances ILC generation in the thymus, and does so by redirecting progenitors to the ILC lineages at the T and ILC developmental branchpoint. Mechanistically, delaying Bcl11b activation promoted ILC redirection by up-regulating a PLZF-dependent ILC transcriptional program in progenitors. Despite up-regulating PLZF, committed ILC progenitors were still capable of later activating Bcl11b, which is also needed for specification of type 2 ILCs. These results show that epigenetic switches, by controlling the activation timing and order of lineage-specifying genes within regulatory networks, can modulate population sizes and proportions of differentiated cell types.

developmental biology↗

bioRxiv2020

Allele-specific gene regulation by KDM6A

KDM6A demethylates the repressive histone mark H3K27me3 and thus plays an important role in developmental gene regulation. KDM6A expression is female-biased due to escape from X inactivation, suggesting that this protein may play a role in sex differences. Here, we report that maternal and paternal alleles of a subset of mouse genes are differentially regulated by KDM6A. Knockouts of Kdm6a in male and female embryonic stem cells derived from F1 hybrid mice from reciprocal interspecific crosses resulted in preferential downregulation of maternal alleles of a number of genes implicated in development. Moreover, the majority of these genes exhibited a maternal allele expression bias, which was observed in both reciprocal crosses. Promoters of genes downregulated on maternal but not paternal alleles demonstrated a loss of chromatin accessibility, while the expected increase in H3K27me3 levels occurred only at promoters of genes downregulated on paternal but not maternal alleles. These results illustrate parent-of-origin mechanisms of gene regulation by KDM6A, consistent with histone demethylation-dependent and -independent activities.

molecular biology↗