Inhibitor of Differentiation 4 (ID4) represses mammary myoepithelial differentiation via inhibition of HEB

Holly Holliday; Daniel Roden; Simon Junankar; Sunny Z. Wu; Laura A. Baker; Christoph Krisp; Chia-Ling Chan; Andrea McFarland; Joanna N. Skhinas; Thomas R. Cox; Bhupinder Pal; Nicholas D. Huntington; Christopher J. Ormandy; Jason S. Carroll; Jane Visvader; Mark P. Molloy; Alexander Swarbrick

doi:10.1016/j.isci.2021.102072

Inhibitor of Differentiation 4 (ID4) represses mammary myoepithelial differentiation via inhibition of HEB

Holly Holliday, Daniel Roden, Simon Junankar, Sunny Z. Wu, Laura A. Baker, Christoph Krisp, Chia-Ling Chan, Andrea McFarland, Joanna N. Skhinas, Thomas R. Cox, Bhupinder Pal, Nicholas D. Huntington, Christopher J. Ormandy, Jason S. Carroll, Jane Visvader, Mark P. Molloy, Alexander Swarbrick^*

^*Corresponding author for this work

Australian Proteome Analysis Facility (APAF)

Research output: Contribution to journal › Article › peer-review

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Abstract

Inhibitor of differentiation (ID) proteins dimerize with basic HLH (bHLH) transcription factors, repressing transcription of lineage-specification genes across diverse cellular lineages. ID4 is a key regulator of mammary stem cells; however, the mechanism by which it achieves this is unclear. Here, we show that ID4 has a cell autonomous role in preventing myoepithelial differentiation of basal cells in mammary organoids and in vivo. ID4 positively regulates proliferative genes and negatively regulates genes involved in myoepithelial function. Mass spectrometry reveals that ID4 interacts with the bHLH protein HEB, which binds to E-box motifs in regulatory elements of basal developmental genes involved in extracellular matrix and the contractile cytoskeleton. We conclude that high ID4 expression in mammary basal stem cells antagonizes HEB transcriptional activity, preventing myoepithelial differentiation and allowing for appropriate tissue morphogenesis. Downregulation of ID4 during pregnancy modulates gene regulated by HEB, promoting specialization of basal cells into myoepithelial cells.

Original language	English
Article number	102072
Pages (from-to)	1-17
Number of pages	41
Journal	iScience
Volume	24
Issue number	2
DOIs	https://doi.org/10.1016/j.isci.2021.102072
Publication status	Published - 19 Feb 2021

Bibliographical note

Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

cell biology
developmental biology
molecular biology
stem cells research

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10.1016/j.isci.2021.102072

Publisher version (open access)Final published version, 15.6 MBLicence: CC BY-NC-ND

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Holliday, H., Roden, D., Junankar, S., Wu, S. Z., Baker, L. A., Krisp, C., Chan, C.-L., McFarland, A., Skhinas, J. N., Cox, T. R., Pal, B., Huntington, N. D., Ormandy, C. J., Carroll, J. S., Visvader, J., Molloy, M. P., & Swarbrick, A. (2021). Inhibitor of Differentiation 4 (ID4) represses mammary myoepithelial differentiation via inhibition of HEB. iScience, 24(2), 1-17. Article 102072. https://doi.org/10.1016/j.isci.2021.102072

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title = "Inhibitor of Differentiation 4 (ID4) represses mammary myoepithelial differentiation via inhibition of HEB",

abstract = "Inhibitor of differentiation (ID) proteins dimerize with basic HLH (bHLH) transcription factors, repressing transcription of lineage-specification genes across diverse cellular lineages. ID4 is a key regulator of mammary stem cells; however, the mechanism by which it achieves this is unclear. Here, we show that ID4 has a cell autonomous role in preventing myoepithelial differentiation of basal cells in mammary organoids and in vivo. ID4 positively regulates proliferative genes and negatively regulates genes involved in myoepithelial function. Mass spectrometry reveals that ID4 interacts with the bHLH protein HEB, which binds to E-box motifs in regulatory elements of basal developmental genes involved in extracellular matrix and the contractile cytoskeleton. We conclude that high ID4 expression in mammary basal stem cells antagonizes HEB transcriptional activity, preventing myoepithelial differentiation and allowing for appropriate tissue morphogenesis. Downregulation of ID4 during pregnancy modulates gene regulated by HEB, promoting specialization of basal cells into myoepithelial cells.",

keywords = "cell biology, developmental biology, molecular biology, stem cells research",

author = "Holly Holliday and Daniel Roden and Simon Junankar and Wu, {Sunny Z.} and Baker, {Laura A.} and Christoph Krisp and Chia-Ling Chan and Andrea McFarland and Skhinas, {Joanna N.} and Cox, {Thomas R.} and Bhupinder Pal and Huntington, {Nicholas D.} and Ormandy, {Christopher J.} and Carroll, {Jason S.} and Jane Visvader and Molloy, {Mark P.} and Alexander Swarbrick",

note = "Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher. ",

year = "2021",

month = feb,

day = "19",

doi = "10.1016/j.isci.2021.102072",

language = "English",

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Holliday, H, Roden, D, Junankar, S, Wu, SZ, Baker, LA, Krisp, C, Chan, C-L, McFarland, A, Skhinas, JN, Cox, TR, Pal, B, Huntington, ND, Ormandy, CJ, Carroll, JS, Visvader, J, Molloy, MP & Swarbrick, A 2021, 'Inhibitor of Differentiation 4 (ID4) represses mammary myoepithelial differentiation via inhibition of HEB', iScience, vol. 24, no. 2, 102072, pp. 1-17. https://doi.org/10.1016/j.isci.2021.102072

TY - JOUR

T1 - Inhibitor of Differentiation 4 (ID4) represses mammary myoepithelial differentiation via inhibition of HEB

AU - Holliday, Holly

AU - Roden, Daniel

AU - Junankar, Simon

AU - Wu, Sunny Z.

AU - Baker, Laura A.

AU - Krisp, Christoph

AU - Chan, Chia-Ling

AU - McFarland, Andrea

AU - Skhinas, Joanna N.

AU - Cox, Thomas R.

AU - Pal, Bhupinder

AU - Huntington, Nicholas D.

AU - Ormandy, Christopher J.

AU - Carroll, Jason S.

AU - Visvader, Jane

AU - Molloy, Mark P.

AU - Swarbrick, Alexander

N1 - Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2021/2/19

Y1 - 2021/2/19

N2 - Inhibitor of differentiation (ID) proteins dimerize with basic HLH (bHLH) transcription factors, repressing transcription of lineage-specification genes across diverse cellular lineages. ID4 is a key regulator of mammary stem cells; however, the mechanism by which it achieves this is unclear. Here, we show that ID4 has a cell autonomous role in preventing myoepithelial differentiation of basal cells in mammary organoids and in vivo. ID4 positively regulates proliferative genes and negatively regulates genes involved in myoepithelial function. Mass spectrometry reveals that ID4 interacts with the bHLH protein HEB, which binds to E-box motifs in regulatory elements of basal developmental genes involved in extracellular matrix and the contractile cytoskeleton. We conclude that high ID4 expression in mammary basal stem cells antagonizes HEB transcriptional activity, preventing myoepithelial differentiation and allowing for appropriate tissue morphogenesis. Downregulation of ID4 during pregnancy modulates gene regulated by HEB, promoting specialization of basal cells into myoepithelial cells.

AB - Inhibitor of differentiation (ID) proteins dimerize with basic HLH (bHLH) transcription factors, repressing transcription of lineage-specification genes across diverse cellular lineages. ID4 is a key regulator of mammary stem cells; however, the mechanism by which it achieves this is unclear. Here, we show that ID4 has a cell autonomous role in preventing myoepithelial differentiation of basal cells in mammary organoids and in vivo. ID4 positively regulates proliferative genes and negatively regulates genes involved in myoepithelial function. Mass spectrometry reveals that ID4 interacts with the bHLH protein HEB, which binds to E-box motifs in regulatory elements of basal developmental genes involved in extracellular matrix and the contractile cytoskeleton. We conclude that high ID4 expression in mammary basal stem cells antagonizes HEB transcriptional activity, preventing myoepithelial differentiation and allowing for appropriate tissue morphogenesis. Downregulation of ID4 during pregnancy modulates gene regulated by HEB, promoting specialization of basal cells into myoepithelial cells.

KW - cell biology

KW - developmental biology

KW - molecular biology

KW - stem cells research

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UR - http://purl.org/au-research/grants/nhmrc/1107671

U2 - 10.1016/j.isci.2021.102072

DO - 10.1016/j.isci.2021.102072

M3 - Article

C2 - 33554073

AN - SCOPUS:85100066950

SN - 2589-0042

VL - 24

SP - 1

EP - 17

JO - iScience

JF - iScience

IS - 2

M1 - 102072

ER -

Inhibitor of Differentiation 4 (ID4) represses mammary myoepithelial differentiation via inhibition of HEB

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