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Basis for Lineage-Determining Pioneer Factors Targeting Distinct Repressed Chromatin States

ABSTRACT: Pioneer transcription factors target compact, transcriptionally silent chromatin, thereby enabling gene activation in development, regeneration, and cell reprogramming. However, silent chromatin is heterogenous, varying in nucleosome mobility, nucleosome compaction, and repressive histone modifications, and how pioneer factors may overcome these different chromatin barriers is unknown. We systematically compared the chromatin targeting of 13 embryonic transcription factors and found that the DNA binding domain (DBD) type predicts whether a pioneer factor targets low-turnover nucleosomes in compact chromatin, dynamic nucleosomes in compact chromatin, or function as non-pioneer factors targeting accessible chromatin. By contrast, non-DBD domains enable targeting of repressed chromatin marked by H3K9me3 or H3K27me3. Fusions of different non-DBD segments of heterochromatin-targeting pioneer factors onto SOX2 can expand binding of Sox2 target motifs, including within heterochromatin, and improve cellular reprogramming. Our study unveils how different forms of silent chromatin are coordinately targeted by lineage-specifying factors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299017 | GEO | 2025/12/03

REPOSITORIES: GEO

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Distinct Chromatin Scanning Modes Lead to Targeting of Compacted Chromatin by Pioneer Factors FOXA1 and SOX2 [Cut&Run]

Project description:Pioneer transcription factors, by interacting with nucleosomes, scan silent, compact chromatin to target regulatory sequences, enabling cooperative binding events that modulate local chromatin structure and gene activity. However, not all cognate motifs are targeted by pioneer factors and dynamic scanning parameters required to scan compact chromatin are unknown. A combined genomics and single-molecule tracking approach shows that to target DNase-resistant, low-histone turnover sites, pioneer factors FOXA1 and SOX2 display opposite dynamics of chromatin scanning: slow, with low nucleoplasmic diffusion and stable interactions, versus fast, with high nucleoplasmic diffusion and transient interactions, respectively. Despite such differences, the ability of FOXA1 and SOX2 to scan low-mobility chromatin, mediated by protein domains outside of the respective DNA binding domains, leads to targeting silent chromatin. By contrast, non-pioneer HNF4A predominantly targets DNase-sensitive, nucleosome-depleted regions. We conclude that the targeting of compact chromatin sites by pioneer factors can be performed through diverse dynamic processes. Cleavage under Targets and Release Using Nuclease (CUT&RUN) of SOX2 and SOX2-DBD after ectopic expression in BJ fibroblasts.

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Distinct Chromatin Scanning Modes Lead to Targeting of Compacted Chromatin by Pioneer Factors FOXA1 and SOX2 [Mnase-seq]

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Pax7 pioneer factor action requires both paired and homeo DNA binding domains [ATAC-seq]

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Pax7 pioneer factor action requires both paired and homeo DNA binding domains [ChIP-seq]

2021-07-28 | GSE173740 | GEO

Pax7 pioneer factor action requires both paired and homeo DNA binding domains [Mnase-seq]

2021-07-28 | GSE173742 | GEO

Different chromatin scanning modes lead to targeting of compacted chromatin by pioneer factors FOXA1 and SOX2

Project description:Different chromatin scanning modes lead to targeting of compacted chromatin by pioneer factors FOXA1 and SOX2

| PRJNA910201 | ENA

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