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<p>Control of gene expression is commonly mediated by distinct combinations of transcription factors (TFs). This cooperative action allows the integration of multiple biological signals at regulatory elements, resulting in highly specific gene expression patterns. It is unclear whether combinatorial binding is also necessary to bring together TFs with distinct biochemical functions, which collaborate to effectively recruit and activate RNA polymerase II. Using a cardiac differentiation model, we find that the largely ubiquitous homeodomain proteins MEIS act as actuators, fully activating transcriptional programs selected by lineage-restricted TFs. Combinatorial binding of MEIS with lineage-enriched TFs, GATA, and HOX, provides selectivity, guiding MEIS to function at cardiac-specific enhancers. In turn, MEIS TFs promote the accumulation of the methyltransferase KMT2D to initiate lineage-specific enhancer commissioning. MEIS combinatorial binding dynamics, dictated by the changing dosage of its partners, drive cells into progressive stages of differentiation. Our results uncover tissue-specific transcriptional activation as the result of ubiquitous actuator TFs harnessing general transcriptional activator at tissue-specific enhancers, to which they are directed by binding with lineage- and domain-specific TFs.</p>

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Ubiquitous MEIS transcription factors actuate lineage-specific transcription to establish cell fate

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月28日

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  • Zoulfia Darieva,
  • Peyman Zarrineh,
  • Naomi Phillips,
  • Joshua Mallen,
  • Araceli Garcia Mora,
  • Ian Donaldson,
  • Laure Bridoux,
  • Megan Douglas,
  • Sara F Dias Henriques,
  • Dorothea Schulte,
  • Matthew J Birket,
  • Nicoletta Bobola

摘要

Control of gene expression is commonly mediated by distinct combinations of transcription factors (TFs). This cooperative action allows the integration of multiple biological signals at regulatory elements, resulting in highly specific gene expression patterns. It is unclear whether combinatorial binding is also necessary to bring together TFs with distinct biochemical functions, which collaborate to effectively recruit and activate RNA polymerase II. Using a cardiac differentiation model, we find that the largely ubiquitous homeodomain proteins MEIS act as actuators, fully activating transcriptional programs selected by lineage-restricted TFs. Combinatorial binding of MEIS with lineage-enriched TFs, GATA, and HOX, provides selectivity, guiding MEIS to function at cardiac-specific enhancers. In turn, MEIS TFs promote the accumulation of the methyltransferase KMT2D to initiate lineage-specific enhancer commissioning. MEIS combinatorial binding dynamics, dictated by the changing dosage of its partners, drive cells into progressive stages of differentiation. Our results uncover tissue-specific transcriptional activation as the result of ubiquitous actuator TFs harnessing general transcriptional activator at tissue-specific enhancers, to which they are directed by binding with lineage- and domain-specific TFs.