Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay.

In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells phenotypically and transcriptionally similar to those found in human tumors.

scooby: Modeling multi-modal genomic profiles from DNA sequence at single-cell resolution.

Understanding how regulatory DNA elements shape gene expression across individual cells is a fundamental challenge in genomics. Joint RNA-seq and epigenomic profiling provides opportunities to build unifying models of gene regulation capturing sequence determinants across steps of gene expression. However, current models, developed primarily for bulk omics data, fail to capture the cellular heterogeneity and dynamic processes revealed by single-cell multi-modal technologies.

BACH2 regulates diversification of regulatory and proinflammatory chromatin states in T17 cells.

Interleukin-17 (IL-17)-producing helper T (T17) cells are heterogenous and consist of nonpathogenic T17 (npT17) cells that contribute to tissue homeostasis and pathogenic T17 (pT17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying T17 heterogeneity and discover substantial differences in the chromatin landscape of npT17 and pT17 cells both in vitro and in vivo. Compared to other CD4 T cell subsets, npT17 cells share accessible chromatin configurations with regulatory T cells, whereas pT17 cells exhibit features of both npT17 cells and type 1 helper T (T1) cells.

Cell of origin epigenetic priming determines susceptibility to Tet2 mutation.

Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigate how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we find that the epigenetic features of clones at similar differentiation status are highly heterogeneous and functionally respond differently to Tet2 mutation.