2. Academic Validation
  3. Composite transposons with bivalent histone marks function as RNA-dependent enhancers in cell fate regulation

Composite transposons with bivalent histone marks function as RNA-dependent enhancers in cell fate regulation

  • Cell. 2025 Jul 29:S0092-8674(25)00803-7. doi: 10.1016/j.cell.2025.07.014.
Ziqiang Zhou 1,  Shicong Zhu 2,  Yaqiang Hong 1,  Guangpu Jin 1,  Rui Ma 3,  Fan Lin 3,  Yiyang Zhang 2,  Hsiang-Ying Lee 4,  Nian Liu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Green Biomanufacturing, Tsinghua-Peking Joint Center for Life Sciences, Center for Synthetic and Systems Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China.
  • 2 State Key Laboratory of Membrane Biology, Peking-Tsinghua Center for Life Sciences, Beijing Advanced Center of RNA Biology, School of Life Sciences, Peking University, Beijing, China.
  • 3 Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.
  • 4 State Key Laboratory of Membrane Biology, Peking-Tsinghua Center for Life Sciences, Beijing Advanced Center of RNA Biology, School of Life Sciences, Peking University, Beijing, China. Electronic address: slee@pku.edu.cn.
  • 5 State Key Laboratory of Green Biomanufacturing, Tsinghua-Peking Joint Center for Life Sciences, Center for Synthetic and Systems Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. Electronic address: liunian88@tsinghua.edu.cn.
PMID: 40774253 DOI: 10.1016/j.cell.2025.07.014
Abstract

Discrete genomic units can recombine into composite transposons that transcribe and transpose as single units, but their regulation and function are not fully understood. We report that composite transposons harbor bivalent histone marks, with activating and repressive marks in distinct regions. Genome-wide CRISPR-Cas9 screening, using a reporter driven by the hominid-specific composite transposon SVA (SINE [short interspersed nuclear element]-VNTR [variable number of tandem repeats]-Alu) in human cells, identified diverse genes that modify bivalent histone marks to regulate SVA transcription. SVA transcripts are critical for SVA's cis-regulatory function in selectively contacting and activating long-range gene expression. Remarkably, a subset of bivalent SVAs is activated during erythropoiesis to boost multiple erythroid gene expression, and knocking down these SVAs leads to deficient erythropoiesis. The RNA-dependent cis-regulatory function of SVA activates genes for myelopoiesis and can contribute to aging-associated myeloid-biased hematopoiesis. These results reveal that the cis-regulatory functions of composite transposons are bivalently regulated to control cell fate transitions in development and aging.

Keywords

RNA-dependent enhancer; SVA; aging; bivalent chromatin; cell fate transition; cis-regulatory elements; composite transposon; erythropoiesis; hematopoiesis; myelopoiesis.

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