Transcription Factor PU.1 Represses and Activates Gene Expression in Early T Cells by Redirecting Partner Transcription Factor Binding

Hosokawa, Hiroyuki; Ungerbäck, Jonas; Wang, Xun; Matsumoto, Masaki; Nakayama, Keiichi I.; Cohen, Sarah M; Tanaka, Tomoaki; Rothenberg, Ellen V.

doi:10.1016/j.immuni.2018.09.019

Cited by 40 publications

(107 citation statements)

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“…4A; Table S5), as shown using acute deletion in the Cas9 transgenic mouse system as described above ( Fig. 2D) (Hosokawa et al 2018). Due to the stability of PU.1 protein (Kueh et al 2013), acute deletion effects are manifest with slower kinetics (days) than effects of introducing an exogenous wildtype or mutant PU.1 (<20 hr) (Champhekar et al 2015).…”

Section: Cas9 Deletion Confirms Shared Targets Of Endogenous and Exogmentioning

confidence: 90%

“…The motifs most highly co-enriched with PU.1 motifs at both activating and repressing sites were for Runx factors. In a related study, we have shown that PU.1 physically interacts with Runx1 in pro-T cells and recruits it to PU.1 binding sites (Hosokawa et al 2018). Fig.…”

Section: Pu1 Can Bind Its Target Sites Independently Of Runx1mentioning

confidence: 90%

“…This treatment effectively disrupted the region around the first Met codon shared by all Runx1 24 isoforms ( Fig. S6C) and eliminated Runx1 protein expression (Hosokawa et al 2018). As for endogenous PU.1 in primary cells, exogenous PU.1 occupancies overlapped pre-existing Runx1 sites (right panel) (Hosokawa et al 2018) much more in regions that were initially open in 2C2 cells than in regions that were closed.…”

Section: Pu1 Can Bind Its Target Sites Independently Of Runx1mentioning

confidence: 96%

“…This protocol deletes targeted exons biallelically ( Fig. S1G) and removes endogenous PU.1 expression (Hosokawa et al 2018). While promoter sites were unaffected, far more non-promoter sites specifically lost accessibility than gained accessibility when PU.1 was deleted, and these sensitive sites were normally open in DN1 but not in DN3 stage ( Fig.…”

Section: Non-promoter Pu1 Sites Control Chromatin Configuration and mentioning

confidence: 99%

“…Fig. 6E shows that a large fraction of endogenous PU.1 occupancy sites that were open in primary DN1 cells were in fact co-occupied by Runx1 [data from (Hosokawa et al 2018)], with highest Runx1 binding enrichment among those sites with lower-quality PU.1 motifs (below median PWM score).…”

Section: Pu1 Can Bind Its Target Sites Independently Of Runx1mentioning

confidence: 99%

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Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by PU.1

Ungerbäck

Hosokawa

Wang

et al. 2018

Preprint

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PU.1 is a dominant but transient regulator in early T-cell precursors and a potent transcriptional controller of developmentally important pro-T cell genes. Before T-lineage commitment, open chromatin is frequently occupied by PU.1, and many PU.1 sites lose accessibility when PU.1 is later downregulated. Pioneering activity of PU.1 was tested in in this developmentally dynamic context, by quantitating the relationships between PU.1 occupancy and site quality and accessibility as PU.1 levels naturally declined in pro-T cell development, and by using stage-specific gain and loss of function perturbations to relate binding to effects on target genes. PU.1 could bind closed genomic sites, but rapidly opened many of them, despite the absence of its frequent collaborators, C/EBP factors. The dynamic properties of PU.1 engagements implied that PU.1 binding affinity and concentration determine its occupancy choices, but with quantitative tradeoffs for occupancy between site sequence quality and stage-dependent site accessibility in chromatin. At non-promoter sites PU.1 binding criteria were more stringent than at promoters, and PU.1 was also much more effective as a transcriptional regulator at non-promoter sites where local chromatin accessibility depended on the presence of PU.1. Runx motifs and Runx1 binding were often linked to PU.1 at open sites, but highly expressed PU.1 could bind its sites without Runx1. Notably, closed chromatin presented a qualitative barrier to occupancy by the PU.1 DNA binding domain alone. Thus, effective pioneering at closed chromatin sites also depends on requirements beyond site recognition served by non-DNA binding domains of PU.1.

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Section: Cas9 Deletion Confirms Shared Targets Of Endogenous and Exogmentioning

confidence: 90%

Section: Pu1 Can Bind Its Target Sites Independently Of Runx1mentioning

confidence: 90%

Section: Pu1 Can Bind Its Target Sites Independently Of Runx1mentioning

confidence: 96%

Section: Non-promoter Pu1 Sites Control Chromatin Configuration and mentioning

confidence: 99%

Section: Pu1 Can Bind Its Target Sites Independently Of Runx1mentioning

confidence: 99%

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Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by PU.1

Ungerbäck

Hosokawa

Wang

et al. 2018

Preprint

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Transcription factors regulate early T cell development via redeployment of other factors

2021

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Establishment of cell lineage identity from multipotent progenitors is controlled by cooperative actions of lineage-specific and stably expressed transcription factors, combined with input from environmental signals. Lineage-specific master transcription factors activate and repress gene expression by recruiting consistently expressed transcription factors and chromatin modifiers to their target loci. Recent technical advances in genome-wide and multi-omics analysis have shed light on unexpected mechanisms that underlie more complicated actions of transcription factors in cell fate decisions. In this review, we discuss functional dynamics of stably expressed and continuously required factors, Notch and Runx family members, throughout developmental stages of early T cell development in the thymus. Pre-and post-commitment stagespecific transcription factors induce dynamic redeployment of Notch and Runx binding genomic regions. Thus, together with stage-specific transcription factors, shared transcription factors across distinct developmental stages regulate acquisition of T lineage identity.

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miR‐191 modulates B‐cell development and targets transcription factors E2A, Foxp1, and Egr1

et al. 2018

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The interdependence of posttranscriptional gene regulation via miRNA and transcriptional regulatory networks in lymphocyte development is poorly understood. Here, we identified miR-191 as direct upstream modulator of a transcriptional module comprising the transcription factors Foxp1, E2A, and Egr1. Deletion as well as ectopic expression of miR-191 resulted in developmental arrest in B lineage cells, indicating that fine tuning of the combined expression levels of Foxp1, E2A, and Egr1, which in turn control somatic recombination and cytokine-driven expansion, constitutes a prerequisite for efficient Bcell development. In conclusion, we propose that miR-191 acts as a rheostat in B-cell development by fine tuning a key transcriptional program.Keywords: B cells r Lymphocyte development r miRNA r miR-191 r Transcriptional factors Additional supporting information may be found online in the Supporting

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Transcription Factor PU.1 Represses and Activates Gene Expression in Early T Cells by Redirecting Partner Transcription Factor Binding

Cited by 40 publications

References 0 publications

Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by PU.1

Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by PU.1

Transcription factors regulate early T cell development via redeployment of other factors

miR‐191 modulates B‐cell development and targets transcription factors E2A, Foxp1, and Egr1

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