Helios is a key transcriptional regulator of outer hair cell maturation

Lauren Chessum; Maggie S. Matern; Michael C. Kelly; Stuart L. Johnson; Yoko Ogawa; Beatrice Milon; Mark McMurray; Elizabeth C. Driver; Andrew Parker; Yang Song; Gemma Codner; Christopher T. Esapa; Jack Prescott; Graham Trent; Sara Wells; Abigail K. Dragich; Gregory I. Frolenkov; Matthew W. Kelley; Walter Marcotti; Steve D.M. Brown; Ran Elkon; Michael R. Bowl; Ronna Hertzano

doi:10.1038/s41586-018-0728-4

Helios is a key transcriptional regulator of outer hair cell maturation

Lauren Chessum, Maggie S. Matern, Michael C. Kelly, Stuart L. Johnson, Yoko Ogawa, Beatrice Milon, Mark McMurray, Elizabeth C. Driver, Andrew Parker, Yang Song, Gemma Codner, Christopher T. Esapa, Jack Prescott, Graham Trent, Sara Wells, Abigail K. Dragich, Gregory I. Frolenkov, Matthew W. Kelley, Walter Marcotti, Steve D.M. BrownRan Elkon, Michael R. Bowl, Ronna Hertzano

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

88 Scopus citations

Abstract

The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning¹. Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2^cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm. Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity.

Original language	English
Pages (from-to)	696-724
Number of pages	29
Journal	Nature
Volume	563
Issue number	7733
DOIs	https://doi.org/10.1038/s41586-018-0728-4
State	Published - 2018

Bibliographical note

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© 2018 Springer Nature Limited. All rights reserved.

Funding

Acknowledgements We thank L. Vizor, J. Sanderson and W. Chien for technical help and Z. Ahmed for comments on the manuscript. This work was supported by Action on Hearing Loss (G65 to M.R.B., R.H., W.M. and S.D.M.B.), Medical Research Council (MC_U142684175 to S.D.M.B.), Wellcome Trust (102892 to W.M.), NIDCD/NIH R01DC013817 and R01DC03544 (R.H.), DOD CDMRP MR130240 (R.H.), NIDCD/NIH T32DC00046 and F31DC016218 (M.S.M.), the Intramural Program at NIDCD DC000059 (M.W.K.), and NIDCD/NIH R01DC014658 (G.I.F.). S.L.J. is a Royal Society University Research Fellow. R.E. is a Faculty Fellow of the Edmond J. Safra Center for Bioinformatics at Tel Aviv University. We thank L. Vizor, J. Sanderson and W. Chien for technical help and Z. Ahmed for comments on the manuscript. This work was supported by Action on Hearing Loss (G65 to M.R.B., R.H., W.M. and S.D.M.B.), Medical Research Council (MC_U142684175 to S.D.M.B.), Wellcome Trust (102892 to W.M.), NIDCD/NIH R01DC013817 and R01DC03544 (R.H.), DOD CDMRP MR130240 (R.H.), NIDCD/NIH T32DC00046 and F31DC016218 (M.S.M.), the Intramural Program at NIDCD DC000059 (M.W.K.), and NIDCD/NIH R01DC014658 (G.I.F.). S.L.J. is a Royal Society University Research Fellow. R.E. is a Faculty Fellow of the Edmond J. Safra Center for Bioinformatics at Tel Aviv University.

Funders	Funder number
Action on Hearing Loss
National Institutes of Health (NIH)
Tel Aviv University
National Institute on Deafness and Other Communication Disorders	R01DC003544, ZIADC000059, T32DC000046, R01DC013817, R01DC014658, F31DC016218
National Institute on Deafness and Other Communication Disorders
Medical Research Council-São Paulo Research Foundation	MC_UP_1502/1, MC_U142684175
Medical Research Council-São Paulo Research Foundation
UK Industrial Decarbonization Research and Innovation Centre	MC_U142684175
UK Industrial Decarbonization Research and Innovation Centre
DOD CDMRP	DC000059, MR130240, R01DC014658, T32DC00046, F31DC016218
Wellcome Trust	102892
Wellcome Trust

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Chessum, L., Matern, M. S., Kelly, M. C., Johnson, S. L., Ogawa, Y., Milon, B., McMurray, M., Driver, E. C., Parker, A., Song, Y., Codner, G., Esapa, C. T., Prescott, J., Trent, G., Wells, S., Dragich, A. K., Frolenkov, G. I., Kelley, M. W., Marcotti, W., ... Hertzano, R. (2018). Helios is a key transcriptional regulator of outer hair cell maturation. Nature, 563(7733), 696-724. https://doi.org/10.1038/s41586-018-0728-4

@article{9e0a5184e752446fb9e1636bbff31a88,

title = "Helios is a key transcriptional regulator of outer hair cell maturation",

abstract = "The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning1. Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm. Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity.",

author = "Lauren Chessum and Matern, \{Maggie S.\} and Kelly, \{Michael C.\} and Johnson, \{Stuart L.\} and Yoko Ogawa and Beatrice Milon and Mark McMurray and Driver, \{Elizabeth C.\} and Andrew Parker and Yang Song and Gemma Codner and Esapa, \{Christopher T.\} and Jack Prescott and Graham Trent and Sara Wells and Dragich, \{Abigail K.\} and Frolenkov, \{Gregory I.\} and Kelley, \{Matthew W.\} and Walter Marcotti and Brown, \{Steve D.M.\} and Ran Elkon and Bowl, \{Michael R.\} and Ronna Hertzano",

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doi = "10.1038/s41586-018-0728-4",

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Chessum, L, Matern, MS, Kelly, MC, Johnson, SL, Ogawa, Y, Milon, B, McMurray, M, Driver, EC, Parker, A, Song, Y, Codner, G, Esapa, CT, Prescott, J, Trent, G, Wells, S, Dragich, AK, Frolenkov, GI, Kelley, MW, Marcotti, W, Brown, SDM, Elkon, R, Bowl, MR & Hertzano, R 2018, 'Helios is a key transcriptional regulator of outer hair cell maturation', Nature, vol. 563, no. 7733, pp. 696-724. https://doi.org/10.1038/s41586-018-0728-4

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T1 - Helios is a key transcriptional regulator of outer hair cell maturation

AU - Chessum, Lauren

AU - Matern, Maggie S.

AU - Kelly, Michael C.

AU - Johnson, Stuart L.

AU - Ogawa, Yoko

AU - Milon, Beatrice

AU - McMurray, Mark

AU - Driver, Elizabeth C.

AU - Parker, Andrew

AU - Song, Yang

AU - Codner, Gemma

AU - Esapa, Christopher T.

AU - Prescott, Jack

AU - Trent, Graham

AU - Wells, Sara

AU - Dragich, Abigail K.

AU - Frolenkov, Gregory I.

AU - Kelley, Matthew W.

AU - Marcotti, Walter

AU - Brown, Steve D.M.

AU - Elkon, Ran

AU - Bowl, Michael R.

AU - Hertzano, Ronna

PY - 2018

Y1 - 2018

N2 - The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning1. Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm. Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity.

AB - The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning1. Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm. Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity.

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Helios is a key transcriptional regulator of outer hair cell maturation

Abstract

Bibliographical note

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