Batf Pioneers the Reorganization of Chromatin in Developing Effector T Cells via Ets1-Dependent Recruitment of Ctcf

Pham, Duy; Moseley, Carson E.; Gao, Min; Savic, Daniel; Winstead, Colleen J.; Sun, Mengxi; Kee, Barbara L.; Myers, R; Weaver, Casey T.; Hatton, Robin D.

doi:10.1016/j.celrep.2019.09.064

Cited by 79 publications

(79 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yet, the functions and binding sites of both factors are only partially overlapping. BATF but not IRF4 can pioneer chromatin in Th17 cells 33 . Moreover, as we show in this report BATF but not IRF4 can cooperate with STAT5 in activating the Il9 locus.…”

Section: Discussionmentioning

confidence: 96%

“…During T-cell activation, AP-1 complexes are important pioneers in generating newly remodeled chromatin 57 . In Th17 and Tr1 cells, BATF, which dimerizes with AP-1 family members, is also thought to be a pioneer factor, based on genome-wide binding and ATAC-seq analyses 33 , 35 . However, BATF still only pioneers a fraction of the complete subset-specific program, suggesting that additional factors must also have pioneer function.…”

Section: Discussionmentioning

confidence: 99%

“…However, the ability of STAT5 to remodel chromatin may be very restricted. It is not clear whether STAT5 impacts as many ATAC-seq peaks as the tens of thousands impacted by AP-1 and BATF 30 , 33 , 57 . It is possible some pioneer factors might have very restricted capabilities that allow extracellular signals to activate subsets of genes involved in differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…BATF is a commonly expressed factor; it is required in multiple lineages including Th2, Th9, Th17, Tfh, and Tr1 cells [27][28][29][30][31][32] . In Th17 and Tr1 cells, BATF has pioneering functions in opening chromatin during the differentiation [33][34][35] . In contrast, ectopic expression of BATF functions in a lineage-specific manner, inducing IL-9 only in cells cultured under Th9-inducing conditions, suggesting that it cannot pioneer plasticity of IL-9 expression in other subsets 28,36 .…”

mentioning

confidence: 99%

See 3 more Smart Citations

STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus

Wang

Panangipalli

et al. 2020

Nat Commun

View full text Add to dashboard Cite

T helper cell differentiation requires lineage-defining transcription factors and factors that have shared expression among multiple subsets. BATF is required for development of multiple Th subsets but functions in a lineage-specific manner. BATF is required for IL-9 production in Th9 cells but in contrast to its function as a pioneer factor in Th17 cells, BATF is neither sufficient nor required for accessibility at the Il9 locus. Here we show that STAT5 is the earliest factor binding and remodeling the Il9 locus to allow BATF binding in both mouse and human Th9 cultures. The ability of STAT5 to mediate accessibility for BATF is observed in other Th lineages and allows acquisition of the IL-9-secreting phenotype. STAT5 and BATF convert Th17 cells into cells that mediate IL-9-dependent effects in allergic airway inflammation and anti-tumor immunity. Thus, BATF requires the STAT5 signal to mediate plasticity at the Il9 locus.

show abstract

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus

Wang

Panangipalli

et al. 2020

Nat Commun

View full text Add to dashboard Cite

show abstract

“…Most T EFF -associated genes and their cognate cis-regulatory regions are inaccessible to these TFs in the T N state, therefore, the role of effector-driving TFs must be linked to chromatin accessibility changes that occur during the T N to T EFF transition. Indeed, there is emerging evidence that some of these early operating TFs, such as Batf, may contribute to T EFF gene accessibility through chromatin remodeling (Pham et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

In vivoCRISPR screening identifies Fli1 as a transcriptional safeguard that restrains effector CD8 T cell differentiation during infection and cancer

Chen

Arai

Khan

et al. 2020

Preprint

View full text Add to dashboard Cite

Improving effector activity of antigen specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (T EFF )-driving transcription factors (TF), the transcriptional coordination of T EFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a novel mechanism restraining T EFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced T EFF responses without compromising memory or exhaustion precursors. Fli1 restrained T EFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs allowing more efficient Runx3-driven T EFF biology. CD8 T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8 T cell transcriptional landscape from excessive ETS:RUNX-driven T EFF cell differentiation. Moreover, genetic deletion of Fli1 improves T EFF differentiation and protective immunity in infections and cancer. Utzschneider et al., 2016; Wu et al., 2016; Zhou et al., 2010) TCF-1 represses (directly or indirectly) T EFF -driving TF such as T-bet and Blimp-1(Tiemessen et al., 2014), and may also have a role in enabling epigenetic changes (Xing et al., 2016). Moreover, a second HMG TF, Tox, is essential for the development of the T EX cell fate by promoting T EX differentiation and repressing of the T EFF lineage differentiation(Alfei et al., 2019; Khan et al., 2019; Scott et al., 2019; Seo et al., 2019; Yao et al., 2019). Tox reprograms the open chromatin landscape, inducing global T EX -specific epigenetic changes and repressing chromatin accessibility associated with T EFF differentiation, in part by recruiting epigenetic modifiers including the lysine acetyltransferase Kat7 (Khan et al., 2019). Despite this work, mechanisms that safeguard against commitment to T EFF differentiation remain poorly understood. Such information could be of considerable utility for immunotherapies focused on enhancing anti-tumor or antiviral activity. However, whereas inactivating pathways like TCF-1 or Tox that would de-repress the entire program of T EFF differentiation are of interest, such approaches result in terminal T EFF and may have limited therapeutic benefit because such cells cannot sustain durable responses. Thus, the discovery of mechanisms that selectively de-repress key aspects of T EFF differentiation, particularly those involved in control of numerical expansion and/or protective immunity would be of considerable interest.Here, we used in vivo CRISPR-Cas9 screening in antigen-specific CD8 T cells responding to acute or chronic viral infection to identify key regulators of T EFF and T EX . In particular, we were interested in identifying genes that resulted by gain-of-function, improving T EFF differentiation (i.e. an "Up" screen (Kaelin, 2017)). The CRISPR-Cas9 system has been used to interrogate the cancer-imm...

show abstract

BATF is Required for Treg Homeostasis and Stability to Prevent Autoimmune Pathology

Khatun,

Wu,

et al. 2023

Advanced Science

View full text Add to dashboard Cite

Regulatory T (Treg) cells are inevitable to prevent deleterious immune responses to self and commensal microorganisms. Treg function requires continuous expression of the transcription factor (TF) FOXP3 and is divided into two major subsets: resting (rTregs) and activated (aTregs). Continuous T cell receptor (TCR) signaling plays a vital role in the differentiation of aTregs from their resting state, and in their immune homeostasis. The process by which Tregs differentiate, adapt tissue specificity, and maintain stable phenotypic expression at the transcriptional level is still inconclusivei. In this work, the role of BATF is investigated, which is induced in response to TCR stimulation in naïve T cells and during aTreg differentiation. Mice lacking BATF in Tregs developed multiorgan autoimmune pathology. As a transcriptional regulator, BATF is required for Treg differentiation, homeostasis, and stabilization of FOXP3 expression in different lymphoid and non‐lymphoid tissues. Epigenetically, BATF showed direct regulation of Treg‐specific genes involved in differentiation, maturation, and tissue accumulation. Most importantly, FOXP3 expression and Treg stability require continuous BATF expression in Tregs, as it regulates demethylation and accessibility of the CNS2 region of the Foxp3 locus. Considering its role in Treg stability, BATF should be considered an important therapeutic target in autoimmune disease.

show abstract

Batf Pioneers the Reorganization of Chromatin in Developing Effector T Cells via Ets1-Dependent Recruitment of Ctcf

Cited by 79 publications

References 70 publications

STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus

STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus

In vivoCRISPR screening identifies Fli1 as a transcriptional safeguard that restrains effector CD8 T cell differentiation during infection and cancer

BATF is Required for Treg Homeostasis and Stability to Prevent Autoimmune Pathology

Contact Info

Product

Resources

About