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A network of epigenetic regulators guides developmental haematopoiesis in vivo

Nature Cell Biology volume 15, pages 15161525 (2013) | Download Citation

Abstract

The initiation of cellular programs is orchestrated by key transcription factors and chromatin regulators that activate or inhibit target gene expression. To generate a compendium of chromatin factors that establish the epigenetic code during developmental haematopoiesis, a large-scale reverse genetic screen was conducted targeting orthologues of 425 human chromatin factors in zebrafish. A set of chromatin regulators was identified that target different stages of primitive and definitive blood formation, including factors not previously implicated in haematopoiesis. We identified 15 factors that regulate development of primitive erythroid progenitors and 29 factors that regulate development of definitive haematopoietic stem and progenitor cells. These chromatin factors are associated with SWI/SNF and ISWI chromatin remodelling, SET1 methyltransferase, CBP–p300–HBO1–NuA4 acetyltransferase, HDAC–NuRD deacetylase, and Polycomb repressive complexes. Our work provides a comprehensive view of how specific chromatin factors and their associated complexes play a major role in the establishment of haematopoietic cells in vivo.

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Acknowledgements

We thank O. Tamplin, T. V. Bowman, P. Cahan and C. K. Kaufman for helpful discussions. The work was supported by NIH NIDDK 5R01DK053298-15, NIH NHLBI 5R01HL048801-21, NIH NIDDK 5P30 DK49216-19, NIH NIDDK DK53298-15, NIH NIDDK R24 DK092760-02, HHMI (to L.I.Z.), NIH NHLBI T32 HL066987-09 and NIH NIDDK 1F32DK089876-01 (to K.L.K).

Author information

Author notes

    • Hsuan-Ting Huang
    •  & Katie L. Kathrein

    These authors contributed equally to this work

Affiliations

  1. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Hsuan-Ting Huang
    •  & Leonard I. Zon
  2. Stem Cell Program and Division of Pediatric Hematology/Oncology, Children’s Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA

    • Hsuan-Ting Huang
    • , Katie L. Kathrein
    • , Abby Barton
    • , Zachary Gitlin
    • , Yue-Hua Huang
    • , Thomas P. Ward
    • , Anthony Dibiase
    • , Anhua Song
    • , Yi Zhou
    •  & Leonard I. Zon
  3. Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA

    • Oliver Hofmann
    • , Winston Hide
    •  & Leonard I. Zon
  4. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA

    • Svitlana Tyekucheva
    •  & Winston Hide
  5. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA

    • Svitlana Tyekucheva

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Contributions

H-T.H. and K.L.K. performed all experiments and data analysis. A.B. and Z.G. assisted with morpholino microinjection, WISH and data collection. Y-H.H. assisted with morpholino microinjection. T.P.W., Y.Z., A.S. and A.D. developed the screen database. Y.Z. initiated and assisted with bioinformatic analysis of chromatin factors. O.H. and W.H. generated the protein interaction network. S.T. performed the distribution analysis for the ChIP-seq data. H-T.H. and L.I.Z. conceived the study.

Competing interests

L.I.Z. is a founder and stock holder of Fate, Inc. and Scholar Rock, and a scientific adviser for Stemgent.

Corresponding author

Correspondence to Leonard I. Zon.

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DOI

https://doi.org/10.1038/ncb2870

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