Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin

Takeshi Masuda; Xin Wang; Manami Maeda; Matthew C. Canver; Falak Sher; Alister P.W. Funnell; Chris Fisher; Maria Suciu; Gabriella E. Martyn; Laura J. Norton; Catherine Zhu; Ryo Kurita; Yukio Nakamura; Jian Xu; Douglas R. Higgs; Merlin Crossley; Daniel E. Bauer; Stuart H. Orkin; Peter V. Kharchenko; Takahiro Maeda

doi:10.1126/science.aad3312

Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin

Takeshi Masuda, Xin Wang, Manami Maeda, Matthew C. Canver, Falak Sher, Alister P.W. Funnell, Chris Fisher, Maria Suciu, Gabriella E. Martyn, Laura J. Norton, Catherine Zhu, Ryo Kurita, Yukio Nakamura, Jian Xu, Douglas R. Higgs, Merlin Crossley, Daniel E. Bauer, Stuart H. Orkin, Peter V. Kharchenko^*, Takahiro Maeda^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

302 Citations (Scopus)

Abstract

Genes encoding human β-type globin undergo a developmental switch from embryonic to fetal to adult-type expression. Mutations in the adult form cause inherited hemoglobinopathies or globin disorders, including sickle cell disease and thalassemia. Some experimental results have suggested that these diseases could be treated by induction of fetal-type hemoglobin (HbF). However, the mechanisms that repress HbF in adults remain unclear. We found that the LRF/ZBTB7A transcription factor occupies fetal γ-globin genes and maintains the nucleosome density necessary for γ-globin gene silencing in adults, and that LRF confers its repressive activity through a NuRD repressor complex independent of the fetal globin repressor BCL11A. Our study may provide additional opportunities for therapeutic targeting in the treatment of hemoglobinopathies.

Original language	English
Pages (from-to)	285-289
Journal	Science
Volume	351
Issue number	6270
DOIs	https://doi.org/10.1126/science.aad3312
Publication status	Published - 15 Jan 2016
Externally published	Yes

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Masuda, T., Wang, X., Maeda, M., Canver, M. C., Sher, F., Funnell, A. P. W., Fisher, C., Suciu, M., Martyn, G. E., Norton, L. J., Zhu, C., Kurita, R., Nakamura, Y., Xu, J., Higgs, D. R., Crossley, M., Bauer, D. E., Orkin, S. H., Kharchenko, P. V., & Maeda, T. (2016). Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science, 351(6270), 285-289. https://doi.org/10.1126/science.aad3312

@article{c84a6439807145b5831c4f0571669be6,

title = "Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin",

abstract = "Genes encoding human β-type globin undergo a developmental switch from embryonic to fetal to adult-type expression. Mutations in the adult form cause inherited hemoglobinopathies or globin disorders, including sickle cell disease and thalassemia. Some experimental results have suggested that these diseases could be treated by induction of fetal-type hemoglobin (HbF). However, the mechanisms that repress HbF in adults remain unclear. We found that the LRF/ZBTB7A transcription factor occupies fetal γ-globin genes and maintains the nucleosome density necessary for γ-globin gene silencing in adults, and that LRF confers its repressive activity through a NuRD repressor complex independent of the fetal globin repressor BCL11A. Our study may provide additional opportunities for therapeutic targeting in the treatment of hemoglobinopathies.",

author = "Takeshi Masuda and Xin Wang and Manami Maeda and Canver, {Matthew C.} and Falak Sher and Funnell, {Alister P.W.} and Chris Fisher and Maria Suciu and Martyn, {Gabriella E.} and Norton, {Laura J.} and Catherine Zhu and Ryo Kurita and Yukio Nakamura and Jian Xu and Higgs, {Douglas R.} and Merlin Crossley and Bauer, {Daniel E.} and Orkin, {Stuart H.} and Kharchenko, {Peter V.} and Takahiro Maeda",

year = "2016",

month = jan,

day = "15",

doi = "10.1126/science.aad3312",

language = "English",

volume = "351",

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Masuda, T, Wang, X, Maeda, M, Canver, MC, Sher, F, Funnell, APW, Fisher, C, Suciu, M, Martyn, GE, Norton, LJ, Zhu, C, Kurita, R, Nakamura, Y, Xu, J, Higgs, DR, Crossley, M, Bauer, DE, Orkin, SH, Kharchenko, PV & Maeda, T 2016, 'Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin', Science, vol. 351, no. 6270, pp. 285-289. https://doi.org/10.1126/science.aad3312

TY - JOUR

T1 - Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin

AU - Masuda, Takeshi

AU - Wang, Xin

AU - Maeda, Manami

AU - Canver, Matthew C.

AU - Sher, Falak

AU - Funnell, Alister P.W.

AU - Fisher, Chris

AU - Suciu, Maria

AU - Martyn, Gabriella E.

AU - Norton, Laura J.

AU - Zhu, Catherine

AU - Kurita, Ryo

AU - Nakamura, Yukio

AU - Xu, Jian

AU - Higgs, Douglas R.

AU - Crossley, Merlin

AU - Bauer, Daniel E.

AU - Orkin, Stuart H.

AU - Kharchenko, Peter V.

AU - Maeda, Takahiro

PY - 2016/1/15

Y1 - 2016/1/15

N2 - Genes encoding human β-type globin undergo a developmental switch from embryonic to fetal to adult-type expression. Mutations in the adult form cause inherited hemoglobinopathies or globin disorders, including sickle cell disease and thalassemia. Some experimental results have suggested that these diseases could be treated by induction of fetal-type hemoglobin (HbF). However, the mechanisms that repress HbF in adults remain unclear. We found that the LRF/ZBTB7A transcription factor occupies fetal γ-globin genes and maintains the nucleosome density necessary for γ-globin gene silencing in adults, and that LRF confers its repressive activity through a NuRD repressor complex independent of the fetal globin repressor BCL11A. Our study may provide additional opportunities for therapeutic targeting in the treatment of hemoglobinopathies.

AB - Genes encoding human β-type globin undergo a developmental switch from embryonic to fetal to adult-type expression. Mutations in the adult form cause inherited hemoglobinopathies or globin disorders, including sickle cell disease and thalassemia. Some experimental results have suggested that these diseases could be treated by induction of fetal-type hemoglobin (HbF). However, the mechanisms that repress HbF in adults remain unclear. We found that the LRF/ZBTB7A transcription factor occupies fetal γ-globin genes and maintains the nucleosome density necessary for γ-globin gene silencing in adults, and that LRF confers its repressive activity through a NuRD repressor complex independent of the fetal globin repressor BCL11A. Our study may provide additional opportunities for therapeutic targeting in the treatment of hemoglobinopathies.

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U2 - 10.1126/science.aad3312

DO - 10.1126/science.aad3312

M3 - RGC 21 - Publication in refereed journal

C2 - 26816381

SN - 0036-8075

VL - 351

SP - 285

EP - 289

JO - Science

JF - Science

IS - 6270

ER -

Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin

Abstract

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