Triglia, E. T. | bioRxiv Science

bioRxiv2023

TIM-4 identifies effector B cells expressing an IL-23-driven proinflammatory cytokine module that promotes immune responses

B cells can express pro-inflammatory cytokines that promote a wide variety of immune responses. Here we show that B cells expressing the phosphatidylserine receptor TIM-4, preferentially express IL-17A, as well as IL-22, IL-6, IL-1{beta}, and GM-CSF - a pattern of cytokines reminiscent of pathogenic Th17 cells. Expression of this proinflammatory module requires IL-23R signaling and selective expression of ROR{gamma}t by TIM-4+ B cells. TIM-4+ B cell-derived-IL-17A not only enhances the severity of experimental autoimmune encephalomyelitis (EAE) and promotes allograft rejection but also acts in an autocrine manner to prevent their conversion into IL-10-expressing B cells with regulatory function. Thus, IL-17A acts as an inflammatory mediator and enforces the proinflammatory activity of TIM-4+ B cells. Moreover, TIM-4 serves as a broad marker for ROR{gamma}t-expressing effector B cells (Beff). These findings allow further study of the signals regulating Beff differentiation and effector molecule expression.

immunology↗

bioRxiv2017

Flipping between Polycomb repressed and active transcriptional states introduces noise in gene expression

Polycomb repressive complexes (PRCs) are important histone modifiers, which silence gene expression, yet there exists a subset of PRC-bound genes actively transcribed by RNA polymerase II (RNAPII). It is likely that the role of PRC is to dampen expression of these PRC-active genes. However, it is unclear how this flipping between chromatin states alters the kinetics of transcriptional burst size and frequency relative to genes with exclusively activating marks. To investigate this, we integrate histone modifications and RNAPII states derived from bulk ChIP-seq data with single-cell RNA-sequencing data. We find that PRC-active genes have a greater cell-to-cell variation in expression than active genes with the same mean expression levels, and validate these results by knockout experiments. We also show that PRC-active genes are clustered on chromosomes in both two and three dimensions, and interactions with active enhancers promote a stabilization of gene expression noise. These findings provide new insights into how chromatin regulation modulates stochastic gene expression and transcriptional bursting, with implications for regulation of pluripotency and development.

genomics↗