The rhythms of histones in regeneration: The epigenetic modifications determined by clock genes

doi:10.1111/exd.15005

. 2024 Jan;33(1):e15005.

doi: 10.1111/exd.15005.

The rhythms of histones in regeneration: The epigenetic modifications determined by clock genes

Ericka J D da Silveira^{1

2}, Caio C D S Barros¹, Marco C Bottino³, Rogerio M Castilho^{1

4}, Cristiane Squarize^{1

4}

Affiliations

¹ Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
² Department of Dentistry, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil.
³ Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
⁴ Michigan Medicine, University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA.

PMID: 38284199
PMCID: PMC10865818 (available on 2025-01-01)
DOI: 10.1111/exd.15005

The rhythms of histones in regeneration: The epigenetic modifications determined by clock genes

Ericka J D da Silveira et al. Exp Dermatol. 2024 Jan.

. 2024 Jan;33(1):e15005.

doi: 10.1111/exd.15005.

Authors

Ericka J D da Silveira^{1

2}, Caio C D S Barros¹, Marco C Bottino³, Rogerio M Castilho^{1

4}, Cristiane Squarize^{1

4}

Affiliations

¹ Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
² Department of Dentistry, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil.
³ Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
⁴ Michigan Medicine, University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA.

PMID: 38284199
PMCID: PMC10865818 (available on 2025-01-01)
DOI: 10.1111/exd.15005

Abstract

The evolutionary establishment of an internal biological clock is a primordial event tightly associated with a 24-h period. Changes in the circadian rhythm can affect cellular functions, including proliferation, DNA repair and redox state. Even isolated organs, tissues and cells can maintain an autonomous circadian rhythm. These cell-autonomous molecular mechanisms are driven by intracellular clock genes, such as BMAL1. Little is known about the role of core clock genes and epigenetic modifications in the skin. Our focus was to identify BMAL1-driven epigenetic modifications associated with gene transcription by mapping the acetylation landscape of histones in epithelial cells responding to injury. We explored the role of BMAL1 in epidermal wound and tissue regeneration using a loss-of-function approach in vivo. We worked with BMAL1 knockout mice and a contraction-resistance wound healing protocol, determining the histone modifications using specific antibodies to detect the acetylation levels of histones H3 and H4. We found significant differences in the acetylation levels of histones in both homeostatic and injured skin with deregulated BMAL1. The intact skin displayed varied acetylation levels of histones H3 and H4, including hyperacetylation of H3 Lys 9 (H3K9). The most pronounced changes were observed at the repair site, with notable alterations in the acetylation pattern of histone H4. These findings reveal the importance of histone modifications in response to injury and indicate that modulation of BMAL1 and its associated epigenetic events could be therapeutically harnessed to improve skin regeneration.

Keywords: epidermis; histone; repair; wound.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

The authors have no conflict of interest with the subject matter or materials discussed in the manuscript.

References

1. Fagiani F, Di Marino D, Romagnoli A, et al. Molecular regulations of circadian rhythm and implications for physiology and diseases. Signal Transduct Target Ther. 2022;7(1):41. doi:10.1038/s41392-022-00899-y - DOI - PMC - PubMed
1. Welz PS, Zinna VM, Symeonidi A, et al. BMAL1-driven tissue clocks respond independently to light to maintain homeostasis. Cell. 2019;177(6):1436–1447 e12. doi:10.1016/j.cell.2019.05.009 - DOI - PMC - PubMed
1. Koike N, Yoo SH, Huang HC, et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science. 2012;338(6105):349–354. doi:10.1126/science.1226339 - DOI - PMC - PubMed
1. Vollmers C, Schmitz RJ, Nathanson J, Yeo G, Ecker JR, Panda S. Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome. Cell Metab. 2012;16(6):833–845. doi:10.1016/j.cmet.2012.11.004 - DOI - PMC - PubMed
1. Rey G, Cesbron F, Rougemont J, Reinke H, Brunner M, Naef F. Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver. PLoS Biol. 2011;9(2):e1000595. doi:10.1371/journal.pbio.1000595 - DOI - PMC - PubMed

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[1] Fagiani F, Di Marino D, Romagnoli A, et al. Molecular regulations of circadian rhythm and implications for physiology and diseases. Signal Transduct Target Ther. 2022;7(1):41. doi:10.1038/s41392-022-00899-y - DOI - PMC - PubMed

[2] Fagiani F, Di Marino D, Romagnoli A, et al. Molecular regulations of circadian rhythm and implications for physiology and diseases. Signal Transduct Target Ther. 2022;7(1):41. doi:10.1038/s41392-022-00899-y - DOI - PMC - PubMed

[3] Welz PS, Zinna VM, Symeonidi A, et al. BMAL1-driven tissue clocks respond independently to light to maintain homeostasis. Cell. 2019;177(6):1436–1447 e12. doi:10.1016/j.cell.2019.05.009 - DOI - PMC - PubMed

[4] Welz PS, Zinna VM, Symeonidi A, et al. BMAL1-driven tissue clocks respond independently to light to maintain homeostasis. Cell. 2019;177(6):1436–1447 e12. doi:10.1016/j.cell.2019.05.009 - DOI - PMC - PubMed

[5] Koike N, Yoo SH, Huang HC, et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science. 2012;338(6105):349–354. doi:10.1126/science.1226339 - DOI - PMC - PubMed

[6] Koike N, Yoo SH, Huang HC, et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science. 2012;338(6105):349–354. doi:10.1126/science.1226339 - DOI - PMC - PubMed

[7] Vollmers C, Schmitz RJ, Nathanson J, Yeo G, Ecker JR, Panda S. Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome. Cell Metab. 2012;16(6):833–845. doi:10.1016/j.cmet.2012.11.004 - DOI - PMC - PubMed

[8] Vollmers C, Schmitz RJ, Nathanson J, Yeo G, Ecker JR, Panda S. Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome. Cell Metab. 2012;16(6):833–845. doi:10.1016/j.cmet.2012.11.004 - DOI - PMC - PubMed

[9] Rey G, Cesbron F, Rougemont J, Reinke H, Brunner M, Naef F. Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver. PLoS Biol. 2011;9(2):e1000595. doi:10.1371/journal.pbio.1000595 - DOI - PMC - PubMed

[10] Rey G, Cesbron F, Rougemont J, Reinke H, Brunner M, Naef F. Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver. PLoS Biol. 2011;9(2):e1000595. doi:10.1371/journal.pbio.1000595 - DOI - PMC - PubMed

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The rhythms of histones in regeneration: The epigenetic modifications determined by clock genes

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The rhythms of histones in regeneration: The epigenetic modifications determined by clock genes

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