Lung stem cell self-renewal relies on BMI1-dependent control of expression at imprinted loci

Sima J. Zacharek; Christine M. Fillmore; Allison N. Lau; David W. Gludish; Alan Chou; Joshua W.K. Ho; Raffaella Zamponi; Roi Gazit; Christoph Bock; Natalie Jäger; Zachary D. Smith; Tae Min Kim; Arven H. Saunders; Janice Wong; Joo Hyeon Lee; Rebecca R. Roach; Derrick J. Rossi; Alex Meissner; Alexander A. Gimelbrant; Peter J. Park; Carla F. Kim

doi:10.1016/j.stem.2011.07.007

Lung stem cell self-renewal relies on BMI1-dependent control of expression at imprinted loci

Sima J. Zacharek, Christine M. Fillmore, Allison N. Lau, David W. Gludish, Alan Chou, Joshua W.K. Ho, Raffaella Zamponi, Roi Gazit, Christoph Bock, Natalie Jäger, Zachary D. Smith, Tae Min Kim, Arven H. Saunders, Janice Wong, Joo Hyeon Lee, Rebecca R. Roach, Derrick J. Rossi, Alex Meissner, Alexander A. Gimelbrant, Peter J. ParkCarla F. Kim

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106 Scopus citations

Abstract

BMI1 is required for the self-renewal of stem cells in many tissues including the lung epithelial stem cells, Bronchioalveolar Stem Cells (BASCs). Imprinted genes, which exhibit expression from only the maternally or paternally inherited allele, are known to regulate developmental processes, but what their role is in adult cells remains a fundamental question. Many imprinted genes were derepressed in Bmi1 knockout mice, and knockdown of Cdkn1c (p57) and other imprinted genes partially rescued the self-renewal defect of Bmi1 mutant lung cells. Expression of p57 and other imprinted genes was required for lung cell self-renewal in culture and correlated with repair of lung epithelial cell injury in vivo. Our data suggest that BMI1-dependent regulation of expressed alleles at imprinted loci, distinct from imprinting per se, is required for control of lung stem cells. We anticipate that the regulation and function of imprinted genes is crucial for self-renewal in diverse adult tissue-specific stem cells.

Original language	English
Pages (from-to)	272-281
Number of pages	10
Journal	Cell Stem Cell
Volume	9
Issue number	3
DOIs	https://doi.org/10.1016/j.stem.2011.07.007
State	Published - Sep 2 2011

Bibliographical note

Funding Information:
We thank Kim Lab members for discussions; S. Temple, C. Dulac, C. Gregg, D. Tenen, C. Hetherington, S. Elledge, J. Luo, N. Solimini, M. Hemann, C. Meacham, and B. Wilson for reagents and discussions; DFCI and CHB HemOnc FACS facilities; CHB Molecular Genetics Core facility; R. Bronson for histology; L. Zon, S. Orkin, and G. Daley for critical reading; and M. Goodell for sharing unpublished data. This work was supported by the Ladies Auxiliary to the Veterans of Foreign Wars (C.M.F.), the National Defense Science & Engineering Graduate Fellowship (A.N.L.), RO1 HL090136, U01 HL100402, American Cancer Society Research Scholar Grant #RSG-08-082-01-MGO, the V Foundation for Cancer Research, a Basil O'Conner March of Dimes Starter Award, and the Harvard Stem Cell Institute (C.F.K.).

Funding

We thank Kim Lab members for discussions; S. Temple, C. Dulac, C. Gregg, D. Tenen, C. Hetherington, S. Elledge, J. Luo, N. Solimini, M. Hemann, C. Meacham, and B. Wilson for reagents and discussions; DFCI and CHB HemOnc FACS facilities; CHB Molecular Genetics Core facility; R. Bronson for histology; L. Zon, S. Orkin, and G. Daley for critical reading; and M. Goodell for sharing unpublished data. This work was supported by the Ladies Auxiliary to the Veterans of Foreign Wars (C.M.F.), the National Defense Science & Engineering Graduate Fellowship (A.N.L.), RO1 HL090136, U01 HL100402, American Cancer Society Research Scholar Grant #RSG-08-082-01-MGO, the V Foundation for Cancer Research, a Basil O'Conner March of Dimes Starter Award, and the Harvard Stem Cell Institute (C.F.K.).

Funders	Funder number
Basil O'Conner March of Dimes
Ladies Auxiliary
American Society for Engineering Education’s National Defense Science and Engineering	U01 HL100402, RO1 HL090136
Veterans of Foreign Wars
American Cancer Society	-08-082-01
National Heart, Lung, and Blood Institute (NHLBI)	U01HL100402
V Foundation for Cancer Research
Harvard Stem Cell Institute

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2011.07.007

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Zacharek, S. J., Fillmore, C. M., Lau, A. N., Gludish, D. W., Chou, A., Ho, J. W. K., Zamponi, R., Gazit, R., Bock, C., Jäger, N., Smith, Z. D., Kim, T. M., Saunders, A. H., Wong, J., Lee, J. H., Roach, R. R., Rossi, D. J., Meissner, A., Gimelbrant, A. A., ... Kim, C. F. (2011). Lung stem cell self-renewal relies on BMI1-dependent control of expression at imprinted loci. Cell Stem Cell, 9(3), 272-281. https://doi.org/10.1016/j.stem.2011.07.007

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title = "Lung stem cell self-renewal relies on BMI1-dependent control of expression at imprinted loci",

abstract = "BMI1 is required for the self-renewal of stem cells in many tissues including the lung epithelial stem cells, Bronchioalveolar Stem Cells (BASCs). Imprinted genes, which exhibit expression from only the maternally or paternally inherited allele, are known to regulate developmental processes, but what their role is in adult cells remains a fundamental question. Many imprinted genes were derepressed in Bmi1 knockout mice, and knockdown of Cdkn1c (p57) and other imprinted genes partially rescued the self-renewal defect of Bmi1 mutant lung cells. Expression of p57 and other imprinted genes was required for lung cell self-renewal in culture and correlated with repair of lung epithelial cell injury in vivo. Our data suggest that BMI1-dependent regulation of expressed alleles at imprinted loci, distinct from imprinting per se, is required for control of lung stem cells. We anticipate that the regulation and function of imprinted genes is crucial for self-renewal in diverse adult tissue-specific stem cells.",

author = "Zacharek, {Sima J.} and Fillmore, {Christine M.} and Lau, {Allison N.} and Gludish, {David W.} and Alan Chou and Ho, {Joshua W.K.} and Raffaella Zamponi and Roi Gazit and Christoph Bock and Natalie J{\"a}ger and Smith, {Zachary D.} and Kim, {Tae Min} and Saunders, {Arven H.} and Janice Wong and Lee, {Joo Hyeon} and Roach, {Rebecca R.} and Rossi, {Derrick J.} and Alex Meissner and Gimelbrant, {Alexander A.} and Park, {Peter J.} and Kim, {Carla F.}",

note = "Funding Information: We thank Kim Lab members for discussions; S. Temple, C. Dulac, C. Gregg, D. Tenen, C. Hetherington, S. Elledge, J. Luo, N. Solimini, M. Hemann, C. Meacham, and B. Wilson for reagents and discussions; DFCI and CHB HemOnc FACS facilities; CHB Molecular Genetics Core facility; R. Bronson for histology; L. Zon, S. Orkin, and G. Daley for critical reading; and M. Goodell for sharing unpublished data. This work was supported by the Ladies Auxiliary to the Veterans of Foreign Wars (C.M.F.), the National Defense Science & Engineering Graduate Fellowship (A.N.L.), RO1 HL090136, U01 HL100402, American Cancer Society Research Scholar Grant #RSG-08-082-01-MGO, the V Foundation for Cancer Research, a Basil O'Conner March of Dimes Starter Award, and the Harvard Stem Cell Institute (C.F.K.). ",

year = "2011",

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doi = "10.1016/j.stem.2011.07.007",

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Zacharek, SJ, Fillmore, CM, Lau, AN, Gludish, DW, Chou, A, Ho, JWK, Zamponi, R, Gazit, R, Bock, C, Jäger, N, Smith, ZD, Kim, TM, Saunders, AH, Wong, J, Lee, JH, Roach, RR, Rossi, DJ, Meissner, A, Gimelbrant, AA, Park, PJ & Kim, CF 2011, 'Lung stem cell self-renewal relies on BMI1-dependent control of expression at imprinted loci', Cell Stem Cell, vol. 9, no. 3, pp. 272-281. https://doi.org/10.1016/j.stem.2011.07.007

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T1 - Lung stem cell self-renewal relies on BMI1-dependent control of expression at imprinted loci

AU - Zacharek, Sima J.

AU - Fillmore, Christine M.

AU - Lau, Allison N.

AU - Gludish, David W.

AU - Chou, Alan

AU - Ho, Joshua W.K.

AU - Zamponi, Raffaella

AU - Gazit, Roi

AU - Bock, Christoph

AU - Jäger, Natalie

AU - Smith, Zachary D.

AU - Kim, Tae Min

AU - Saunders, Arven H.

AU - Wong, Janice

AU - Lee, Joo Hyeon

AU - Roach, Rebecca R.

AU - Rossi, Derrick J.

AU - Meissner, Alex

AU - Gimelbrant, Alexander A.

AU - Park, Peter J.

AU - Kim, Carla F.

N1 - Funding Information: We thank Kim Lab members for discussions; S. Temple, C. Dulac, C. Gregg, D. Tenen, C. Hetherington, S. Elledge, J. Luo, N. Solimini, M. Hemann, C. Meacham, and B. Wilson for reagents and discussions; DFCI and CHB HemOnc FACS facilities; CHB Molecular Genetics Core facility; R. Bronson for histology; L. Zon, S. Orkin, and G. Daley for critical reading; and M. Goodell for sharing unpublished data. This work was supported by the Ladies Auxiliary to the Veterans of Foreign Wars (C.M.F.), the National Defense Science & Engineering Graduate Fellowship (A.N.L.), RO1 HL090136, U01 HL100402, American Cancer Society Research Scholar Grant #RSG-08-082-01-MGO, the V Foundation for Cancer Research, a Basil O'Conner March of Dimes Starter Award, and the Harvard Stem Cell Institute (C.F.K.).

PY - 2011/9/2

Y1 - 2011/9/2

N2 - BMI1 is required for the self-renewal of stem cells in many tissues including the lung epithelial stem cells, Bronchioalveolar Stem Cells (BASCs). Imprinted genes, which exhibit expression from only the maternally or paternally inherited allele, are known to regulate developmental processes, but what their role is in adult cells remains a fundamental question. Many imprinted genes were derepressed in Bmi1 knockout mice, and knockdown of Cdkn1c (p57) and other imprinted genes partially rescued the self-renewal defect of Bmi1 mutant lung cells. Expression of p57 and other imprinted genes was required for lung cell self-renewal in culture and correlated with repair of lung epithelial cell injury in vivo. Our data suggest that BMI1-dependent regulation of expressed alleles at imprinted loci, distinct from imprinting per se, is required for control of lung stem cells. We anticipate that the regulation and function of imprinted genes is crucial for self-renewal in diverse adult tissue-specific stem cells.

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Lung stem cell self-renewal relies on BMI1-dependent control of expression at imprinted loci

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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