Inactivation of Histone Chaperone HIRA Unmasks a Link Between Normal Embryonic Development of Melanoblasts and Maintenance of Adult Melanocyte Stem Cells

Farah Jaber‐Hijazi; Rouven Arnold; Karthic Swaminathan; Kathryn Gilroy; Alexander T. Wenzel; Anthony Lagnado; Kristina Kirschner; Neil Robertson; Claire Reid; Neil Fullarton; Jeff Pawlikowski; Taranjit Singh Rai; Ian Baranyk; Christina Huan Shi; Kevin Y. Yip; Karen Blyth; Jill P. Mesirov; Melissa L. Harris; João F. Passos; Laura M. Machesky; Peter D. Adams

doi:10.1111/acel.70070

Inactivation of Histone Chaperone HIRA Unmasks a Link Between Normal Embryonic Development of Melanoblasts and Maintenance of Adult Melanocyte Stem Cells

Farah Jaber‐Hijazi
, Rouven Arnold
, Karthic Swaminathan
, Kathryn Gilroy
, Alexander T. Wenzel
, Anthony Lagnado
, Kristina Kirschner
, Neil Robertson
, Claire Reid
, Neil Fullarton
, Jeff Pawlikowski
, Taranjit Singh Rai
, Ian Baranyk
, Christina Huan Shi
, Kevin Y. Yip
, Karen Blyth
, Jill P. Mesirov
, Melissa L. Harris
, João F. Passos
, Laura M. Machesky

Peter D. Adams

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

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Abstract

Evidence indicates that the integrity of in utero development influences late life healthy or unhealthy aging; however, specific links between them are unclear. Histone chaperone HIRA is thought to play a role in both life stages, and here, we explore this role using the murine pigmentary system by investigating and comparing the effects of its lineage‐specific knockout, either conditionally during embryogenesis or postnatally. Embryonic knockout of Hira in tyrosinase+ neural crest‐derived lineages, including melanoblasts, led to reduced melanoblast numbers during embryogenesis, with single‐cell RNA sequencing analysis indicating evidence of lineage‐specificity defects. This was supported in an in vitro model using melb‐a melanoblasts in which Hira knockdown affected lineage identity and melanoblast differentiation potential, with ATAC‐seq data indicating a role of HIRA in orchestrating chromatin accessibility. Interestingly, however, newborn Hira knockout mice had wild type numbers of differentiated melanocytes, albeit functionally defective, as demonstrated by very mild hypopigmentation of the first hair coat, increased melanocyte telomere‐associated DNA damage foci, and impaired response to proliferative challenge. Moreover, as they aged, mice with embryonic melanoblast Hira knockout displayed marked defects in melanocyte stem cell maintenance and premature hair graying. Importantly, this phenotype was not observed after postnatal inducible knockout, indicating an essential role for HIRA at embryonic stages that is transmitted to adulthood, rather than a direct postnatal requirement within the pigmentary system. This genetic model shows that HIRA function during early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue‐specific stem cells during aging.

Original language	English
Article number	e70070
Pages (from-to)	1-22
Number of pages	22
Journal	Aging Cell
Volume	24
Issue number	7
Early online date	14 May 2025
DOIs	https://doi.org/10.1111/acel.70070
Publication status	Published (in print/issue) - 31 Jul 2025

Bibliographical note

Data Availability Statement

scRNAseq data were deposited in the Gene Expression Omnibus (GEO)
and can be accessed using reviewer token gjmdcmimzdollol through
the following link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?
acc=GSE132545. The GEO record for RNA-seq can be accessed here:
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE267432 and
that for ATAC seq can be accessed here: https://www.ncbi.nlm.nih.gov/
geo/query/acc.cgi?acc=GSE267431 using reviewer token uxypmmeaxdmdjgr. All raw data used to generate the results and figures of this study
are available upon request. This includes scripts used for scRNAseq
analysis, original IHC and IF images, quantification of dermal pigmentation, original Western blot scans, and individual cell counts for
melanoblasts, melanocytes, and McSCs (DCT-LacZ, BrdU, EdU, DCT
immunofluorescence, TAFs, and flow cytometry).

Funding

Funding: Work in the lab of P.D.A. was supported by P01 AG031862-13 and R01 AR078559 and additional funding from the Cancer Research UK Core Funding to the CRUK Glasgow Centre (A25142) and Cancer Research UK Core Funding to the CRUK Scotland Institute (A17196). R.A. was supported by the California Institute for Regenerative Medicine grant EDUC4-12813. L.M.M. was funded by core CRUK grants A15673 and A24452. Work in the lab of J.P.M. was supported by U24 CA220341, U24 CA194107, and U24 CA248457. A.T.W. was supported by NIH grants T15LM011271, F31CA257344, and T32CA067754. A.L. and work in the J.F.P. lab were supported by NIH grants R01AG068048, R01AG82708, UH3CA268103, and P01 AG062413 and The Glenn Foundation For Medical Research. M.L.H. and I.B. were supported by R01 AR078559. C.H.S. and K.Y.Y. were supported by U54 AG079758, R01 AG085498, and R01 CA287114. K.B. was CRUK Core funded (A29799). K.K. was funded by Blood Cancer UK (grant reference 23001), by an EHA Bilateral grant number ID BCG-202209-02649, and by the Mayo Clinic Robert and Arlene Kogod Center on Aging and the Mayo Clinic Department of Hematology. Work in the lab of P.D.A. was supported by P01 AG031862-13 and R01 AR078559 and additional funding from the CRUK Glasgow Centre (A25142) and Core Services at the Cancer Research UK Scotland Institute (A17196). R.A. was supported by the California Institute for Regenerative Medicine grant EDUC4-12813. L.M.M. was funded by core CRUK grants A15673 and A24452. Work in the lab of J.P.M. was supported by U24 CA220341, U24 CA194107, and U24 CA248457. A.T.W. was supported by NIH grants T15LM011271, F31CA257344, and T32CA067754. A.L. and work in the J.F.P. lab were supported by NIH grants R01AG068048, R01AG82708, UH3CA268103, and P01 AG062413 and The Glenn Foundation For Medical Research. M.L.H. and I.B. were supported by R01 AR078559. C.H.S. and K.Y.Y. were supported by U54 AG079758, R01 AG085498, and R01 CA287114. K.B. was CRUK Core funded (A29799). K.K. was funded by Blood Cancer UK (grant reference 23001), by an EHA Bilateral grant number ID BCG-202209-02649, and by the Mayo Clinic Robert and Arlene Kogod Center on Aging and the Mayo Clinic Department of Hematology. We thank members of the Biological Services Unit at CRUK Scotland Institute for help in animal maintenance, members of Histology services, especially Colin Nixon, for help in mouse tissue processing, and Tom Gilbey for help in cell sorting. We would like to thank the University of Pennsylvania High-throughput Biology Core and David C. Schultz for providing shRNA clones and preparations of lentivirus stocks for in vitro experiments. We thank all members of the Adams, Machesky, and Insall labs for critical discussions. Work in the lab of P.D.A. was supported by P01 AG031862‐13 and R01 AR078559 and additional funding from the CRUK Glasgow Centre (A25142) and Core Services at the Cancer Research UK Scotland Institute (A17196). R.A. was supported by the California Institute for Regenerative Medicine grant EDUC4‐12813. L.M.M. was funded by core CRUK grants A15673 and A24452. Work in the lab of J.P.M. was supported by U24 CA220341, U24 CA194107, and U24 CA248457. A.T.W. was supported by NIH grants T15LM011271, F31CA257344, and T32CA067754. A.L. and work in the J.F.P. lab were supported by NIH grants R01AG068048, R01AG82708, UH3CA268103, and P01 AG062413 and The Glenn Foundation For Medical Research. M.L.H. and I.B. were supported by R01 AR078559. C.H.S. and K.Y.Y. were supported by U54 AG079758, R01 AG085498, and R01 CA287114. K.B. was CRUK Core funded (A29799). K.K. was funded by Blood Cancer UK (grant reference 23001), by an EHA Bilateral grant number ID BCG‐202209‐02649, and by the Mayo Clinic Robert and Arlene Kogod Center on Aging and the Mayo Clinic Department of Hematology. We thank members of the Biological Services Unit at CRUK Scotland Institute for help in animal maintenance, members of Histology services, especially Colin Nixon, for help in mouse tissue processing, and Tom Gilbey for help in cell sorting. We would like to thank the University of Pennsylvania High‐throughput Biology Core and David C. Schultz for providing shRNA clones and preparations of lentivirus stocks for in vitro experiments. We thank all members of the Adams, Machesky, and Insall labs for critical discussions. Work in the lab of P.D.A. was supported by P01 AG031862‐13 and R01 AR078559 and additional funding from the Cancer Research UK Core Funding to the CRUK Glasgow Centre (A25142) and Cancer Research UK Core Funding to the CRUK Scotland Institute (A17196). R.A. was supported by the California Institute for Regenerative Medicine grant EDUC4‐12813. L.M.M. was funded by core CRUK grants A15673 and A24452. Work in the lab of J.P.M. was supported by U24 CA220341, U24 CA194107, and U24 CA248457. A.T.W. was supported by NIH grants T15LM011271, F31CA257344, and T32CA067754. A.L. and work in the J.F.P. lab were supported by NIH grants R01AG068048, R01AG82708, UH3CA268103, and P01 AG062413 and The Glenn Foundation For Medical Research. M.L.H. and I.B. were supported by R01 AR078559. C.H.S. and K.Y.Y. were supported by U54 AG079758, R01 AG085498, and R01 CA287114. K.B. was CRUK Core funded (A29799). K.K. was funded by Blood Cancer UK (grant reference 23001), by an EHA Bilateral grant number ID BCG‐202209‐02649, and by the Mayo Clinic Robert and Arlene Kogod Center on Aging and the Mayo Clinic Department of Hematology. Funding:

Funders	Funder number
University of Pennsylvania
23001
A24452, A15673, U24 CA220341, U24 CA248457, EDUC4‐12813, U24 CA194107
Cancer Research UK	A17196, A25142
BCG‐202209‐02649
National Institutes of Health	R01AG82708, R01AG068048, T15LM011271, UH3CA268103, P01 AG062413, T32CA067754, F31CA257344
U54 AG079758, R01 CA287114, A29799, R01 AG085498

Keywords

Animals
Melanocytes/metabolism
Histone Chaperones/metabolism
Mice
Cell Cycle Proteins/metabolism
Mice, Knockout
Embryonic Development/genetics
Cell Differentiation
Transcription Factors/metabolism
Adult Stem Cells/metabolism
Adult Stem Cells
Histone Chaperones
Melanocytes
Embryonic Development
Transcription Factors
Cell Cycle Proteins
Adult Stem Cells - metabolism - cytology
Embryonic Development - genetics
Transcription Factors - metabolism - genetics
Cell Cycle Proteins - metabolism - genetics
Histone Chaperones - metabolism - genetics
Melanocytes - metabolism - cytology

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10.1111/acel.70070

acel.70070.pdfFinal published version, 8.51 MBLicence: CC BY

Cite this

Jaber‐Hijazi, F., Arnold, R., Swaminathan, K., Gilroy, K., Wenzel, A. T., Lagnado, A., Kirschner, K., Robertson, N., Reid, C., Fullarton, N., Pawlikowski, J., Rai, T. S., Baranyk, I., Shi, C. H., Yip, K. Y., Blyth, K., Mesirov, J. P., Harris, M. L., Passos, J. F., ... Adams, P. D. (2025). Inactivation of Histone Chaperone HIRA Unmasks a Link Between Normal Embryonic Development of Melanoblasts and Maintenance of Adult Melanocyte Stem Cells. Aging Cell, 24(7), 1-22. Article e70070. https://doi.org/10.1111/acel.70070

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title = "Inactivation of Histone Chaperone HIRA Unmasks a Link Between Normal Embryonic Development of Melanoblasts and Maintenance of Adult Melanocyte Stem Cells",

abstract = "Evidence indicates that the integrity of in utero development influences late life healthy or unhealthy aging; however, specific links between them are unclear. Histone chaperone HIRA is thought to play a role in both life stages, and here, we explore this role using the murine pigmentary system by investigating and comparing the effects of its lineage‐specific knockout, either conditionally during embryogenesis or postnatally. Embryonic knockout of Hira in tyrosinase+ neural crest‐derived lineages, including melanoblasts, led to reduced melanoblast numbers during embryogenesis, with single‐cell RNA sequencing analysis indicating evidence of lineage‐specificity defects. This was supported in an in vitro model using melb‐a melanoblasts in which Hira knockdown affected lineage identity and melanoblast differentiation potential, with ATAC‐seq data indicating a role of HIRA in orchestrating chromatin accessibility. Interestingly, however, newborn Hira knockout mice had wild type numbers of differentiated melanocytes, albeit functionally defective, as demonstrated by very mild hypopigmentation of the first hair coat, increased melanocyte telomere‐associated DNA damage foci, and impaired response to proliferative challenge. Moreover, as they aged, mice with embryonic melanoblast Hira knockout displayed marked defects in melanocyte stem cell maintenance and premature hair graying. Importantly, this phenotype was not observed after postnatal inducible knockout, indicating an essential role for HIRA at embryonic stages that is transmitted to adulthood, rather than a direct postnatal requirement within the pigmentary system. This genetic model shows that HIRA function during early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue‐specific stem cells during aging.",

keywords = "Animals, Melanocytes/metabolism, Histone Chaperones/metabolism, Mice, Cell Cycle Proteins/metabolism, Mice, Knockout, Embryonic Development/genetics, Cell Differentiation, Transcription Factors/metabolism, Adult Stem Cells/metabolism, Adult Stem Cells, Histone Chaperones, Melanocytes, Embryonic Development, Transcription Factors, Cell Cycle Proteins, Adult Stem Cells - metabolism - cytology, Embryonic Development - genetics, Transcription Factors - metabolism - genetics, Cell Cycle Proteins - metabolism - genetics, Histone Chaperones - metabolism - genetics, Melanocytes - metabolism - cytology",

author = "Farah Jaber‐Hijazi and Rouven Arnold and Karthic Swaminathan and Kathryn Gilroy and Wenzel, \{Alexander T.\} and Anthony Lagnado and Kristina Kirschner and Neil Robertson and Claire Reid and Neil Fullarton and Jeff Pawlikowski and Rai, \{Taranjit Singh\} and Ian Baranyk and Shi, \{Christina Huan\} and Yip, \{Kevin Y.\} and Karen Blyth and Mesirov, \{Jill P.\} and Harris, \{Melissa L.\} and Passos, \{Jo{\~a}o F.\} and Machesky, \{Laura M.\} and Adams, \{Peter D.\}",

note = "{\textcopyright} 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley \& Sons Ltd.",

year = "2025",

month = jul,

day = "31",

doi = "10.1111/acel.70070",

language = "English",

volume = "24",

pages = "1--22",

journal = "Aging Cell",

issn = "1474-9718",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "7",

}

Jaber‐Hijazi, F, Arnold, R, Swaminathan, K, Gilroy, K, Wenzel, AT, Lagnado, A, Kirschner, K, Robertson, N, Reid, C, Fullarton, N, Pawlikowski, J, Rai, TS, Baranyk, I, Shi, CH, Yip, KY, Blyth, K, Mesirov, JP, Harris, ML, Passos, JF, Machesky, LM & Adams, PD 2025, 'Inactivation of Histone Chaperone HIRA Unmasks a Link Between Normal Embryonic Development of Melanoblasts and Maintenance of Adult Melanocyte Stem Cells', Aging Cell, vol. 24, no. 7, e70070, pp. 1-22. https://doi.org/10.1111/acel.70070

TY - JOUR

T1 - Inactivation of Histone Chaperone HIRA Unmasks a Link Between Normal Embryonic Development of Melanoblasts and Maintenance of Adult Melanocyte Stem Cells

AU - Jaber‐Hijazi, Farah

AU - Arnold, Rouven

AU - Swaminathan, Karthic

AU - Gilroy, Kathryn

AU - Wenzel, Alexander T.

AU - Lagnado, Anthony

AU - Kirschner, Kristina

AU - Robertson, Neil

AU - Reid, Claire

AU - Fullarton, Neil

AU - Pawlikowski, Jeff

AU - Rai, Taranjit Singh

AU - Baranyk, Ian

AU - Shi, Christina Huan

AU - Yip, Kevin Y.

AU - Blyth, Karen

AU - Mesirov, Jill P.

AU - Harris, Melissa L.

AU - Passos, João F.

AU - Machesky, Laura M.

AU - Adams, Peter D.

PY - 2025/7/31

Y1 - 2025/7/31

N2 - Evidence indicates that the integrity of in utero development influences late life healthy or unhealthy aging; however, specific links between them are unclear. Histone chaperone HIRA is thought to play a role in both life stages, and here, we explore this role using the murine pigmentary system by investigating and comparing the effects of its lineage‐specific knockout, either conditionally during embryogenesis or postnatally. Embryonic knockout of Hira in tyrosinase+ neural crest‐derived lineages, including melanoblasts, led to reduced melanoblast numbers during embryogenesis, with single‐cell RNA sequencing analysis indicating evidence of lineage‐specificity defects. This was supported in an in vitro model using melb‐a melanoblasts in which Hira knockdown affected lineage identity and melanoblast differentiation potential, with ATAC‐seq data indicating a role of HIRA in orchestrating chromatin accessibility. Interestingly, however, newborn Hira knockout mice had wild type numbers of differentiated melanocytes, albeit functionally defective, as demonstrated by very mild hypopigmentation of the first hair coat, increased melanocyte telomere‐associated DNA damage foci, and impaired response to proliferative challenge. Moreover, as they aged, mice with embryonic melanoblast Hira knockout displayed marked defects in melanocyte stem cell maintenance and premature hair graying. Importantly, this phenotype was not observed after postnatal inducible knockout, indicating an essential role for HIRA at embryonic stages that is transmitted to adulthood, rather than a direct postnatal requirement within the pigmentary system. This genetic model shows that HIRA function during early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue‐specific stem cells during aging.

AB - Evidence indicates that the integrity of in utero development influences late life healthy or unhealthy aging; however, specific links between them are unclear. Histone chaperone HIRA is thought to play a role in both life stages, and here, we explore this role using the murine pigmentary system by investigating and comparing the effects of its lineage‐specific knockout, either conditionally during embryogenesis or postnatally. Embryonic knockout of Hira in tyrosinase+ neural crest‐derived lineages, including melanoblasts, led to reduced melanoblast numbers during embryogenesis, with single‐cell RNA sequencing analysis indicating evidence of lineage‐specificity defects. This was supported in an in vitro model using melb‐a melanoblasts in which Hira knockdown affected lineage identity and melanoblast differentiation potential, with ATAC‐seq data indicating a role of HIRA in orchestrating chromatin accessibility. Interestingly, however, newborn Hira knockout mice had wild type numbers of differentiated melanocytes, albeit functionally defective, as demonstrated by very mild hypopigmentation of the first hair coat, increased melanocyte telomere‐associated DNA damage foci, and impaired response to proliferative challenge. Moreover, as they aged, mice with embryonic melanoblast Hira knockout displayed marked defects in melanocyte stem cell maintenance and premature hair graying. Importantly, this phenotype was not observed after postnatal inducible knockout, indicating an essential role for HIRA at embryonic stages that is transmitted to adulthood, rather than a direct postnatal requirement within the pigmentary system. This genetic model shows that HIRA function during early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue‐specific stem cells during aging.

KW - Animals

KW - Melanocytes/metabolism

KW - Histone Chaperones/metabolism

KW - Mice

KW - Cell Cycle Proteins/metabolism

KW - Mice, Knockout

KW - Embryonic Development/genetics

KW - Cell Differentiation

KW - Transcription Factors/metabolism

KW - Adult Stem Cells/metabolism

KW - Adult Stem Cells

KW - Histone Chaperones

KW - Melanocytes

KW - Embryonic Development

KW - Transcription Factors

KW - Cell Cycle Proteins

KW - Adult Stem Cells - metabolism - cytology

KW - Embryonic Development - genetics

KW - Transcription Factors - metabolism - genetics

KW - Cell Cycle Proteins - metabolism - genetics

KW - Histone Chaperones - metabolism - genetics

KW - Melanocytes - metabolism - cytology

UR - https://www.scopus.com/pages/publications/105005230595

U2 - 10.1111/acel.70070

DO - 10.1111/acel.70070

M3 - Article

C2 - 40669469

SN - 1474-9718

VL - 24

SP - 1

EP - 22

JO - Aging Cell

JF - Aging Cell

IS - 7

M1 - e70070

ER -

Inactivation of Histone Chaperone HIRA Unmasks a Link Between Normal Embryonic Development of Melanoblasts and Maintenance of Adult Melanocyte Stem Cells

Abstract

Bibliographical note

Data Availability Statement

Funding

Keywords

Access to Document

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