Mouse HP1γ regulates TRF1 expression and telomere stability

Emmanouil Stylianakis; Jackson Ping Kei Chan; Pui Pik Law; Yi Jiang; Sanjay Khadayate; Mohammad Mahdi Karimi; Richard Festenstein; Jean-Baptiste Vannier

doi:10.1016/j.lfs.2023.122030

Mouse HP1γ regulates TRF1 expression and telomere stability

Emmanouil Stylianakis, Jackson Ping Kei Chan, Pui Pik Law, Yi Jiang, Sanjay Khadayate, Mohammad Mahdi Karimi, Richard Festenstein, Jean-Baptiste Vannier

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

Abstract

Aims Telomeric repeat-containing RNAs are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of members of the heterochromatin protein 1 (HP1) protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1γ is enriched on gene bodies of actively transcribed human and mouse genes, it is unclear if its transcriptional role is important for HP1γ function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1γ on the transcription of telomere factors and molecules that can affect telomere maintenance. Main methods We investigated the telomere function of HP1γ by using HP1γ deficient mouse embryonic fibroblasts (MEFs). We used gene expression analysis of HP1γ deficient MEFs and validated the molecular and mechanistic consequences of HP1γ loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA immunoprecipitation (DRIP). Key findings Loss of HP1γ in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage (γH2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNA-RNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X. Significance Our results suggest an important transcriptional control by mouse HP1γ of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.

Original language	English
Article number	122030
Journal	Life Sciences
Volume	331
Early online date	24 Aug 2023
DOIs	https://doi.org/10.1016/j.lfs.2023.122030
Publication status	Published - 15 Oct 2023

Keywords

Telomere
HP1
Chromatin
DNA damage
Epigenetics
TERRA

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10.1016/j.lfs.2023.122030Licence: CC BY

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@article{f8d840acb1414591a17becc492dd5764,

title = "Mouse HP1γ regulates TRF1 expression and telomere stability",

abstract = "Aims Telomeric repeat-containing RNAs are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of members of the heterochromatin protein 1 (HP1) protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1γ is enriched on gene bodies of actively transcribed human and mouse genes, it is unclear if its transcriptional role is important for HP1γ function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1γ on the transcription of telomere factors and molecules that can affect telomere maintenance. Main methods We investigated the telomere function of HP1γ by using HP1γ deficient mouse embryonic fibroblasts (MEFs). We used gene expression analysis of HP1γ deficient MEFs and validated the molecular and mechanistic consequences of HP1γ loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA immunoprecipitation (DRIP). Key findings Loss of HP1γ in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage (γH2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNA-RNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X. Significance Our results suggest an important transcriptional control by mouse HP1γ of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.",

keywords = "Telomere, HP1, Chromatin, DNA damage, Epigenetics, TERRA",

author = "Emmanouil Stylianakis and Chan, {Jackson Ping Kei} and Law, {Pui Pik} and Yi Jiang and Sanjay Khadayate and Karimi, {Mohammad Mahdi} and Richard Festenstein and Jean-Baptiste Vannier",

note = "Funding Information: JBV is supported by the London Institute of Medical Sciences (LMS), which receives its core funding from UKRI (MRC) and by an ERC Starter Grant ( 637798 ; MetDNASecStr) and is thankful to Imperial College London for its support. ES is funded by an MRC PhD fellowship. Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = oct,

day = "15",

doi = "10.1016/j.lfs.2023.122030",

language = "English",

volume = "331",

journal = "Life Sciences",

issn = "0024-3205",

publisher = "Elsevier Inc.",

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TY - JOUR

T1 - Mouse HP1γ regulates TRF1 expression and telomere stability

AU - Stylianakis, Emmanouil

AU - Chan, Jackson Ping Kei

AU - Law, Pui Pik

AU - Jiang, Yi

AU - Khadayate, Sanjay

AU - Karimi, Mohammad Mahdi

AU - Festenstein, Richard

AU - Vannier, Jean-Baptiste

N1 - Funding Information: JBV is supported by the London Institute of Medical Sciences (LMS), which receives its core funding from UKRI (MRC) and by an ERC Starter Grant ( 637798 ; MetDNASecStr) and is thankful to Imperial College London for its support. ES is funded by an MRC PhD fellowship. Publisher Copyright: © 2023

PY - 2023/10/15

Y1 - 2023/10/15

N2 - Aims Telomeric repeat-containing RNAs are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of members of the heterochromatin protein 1 (HP1) protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1γ is enriched on gene bodies of actively transcribed human and mouse genes, it is unclear if its transcriptional role is important for HP1γ function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1γ on the transcription of telomere factors and molecules that can affect telomere maintenance. Main methods We investigated the telomere function of HP1γ by using HP1γ deficient mouse embryonic fibroblasts (MEFs). We used gene expression analysis of HP1γ deficient MEFs and validated the molecular and mechanistic consequences of HP1γ loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA immunoprecipitation (DRIP). Key findings Loss of HP1γ in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage (γH2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNA-RNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X. Significance Our results suggest an important transcriptional control by mouse HP1γ of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.

AB - Aims Telomeric repeat-containing RNAs are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of members of the heterochromatin protein 1 (HP1) protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1γ is enriched on gene bodies of actively transcribed human and mouse genes, it is unclear if its transcriptional role is important for HP1γ function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1γ on the transcription of telomere factors and molecules that can affect telomere maintenance. Main methods We investigated the telomere function of HP1γ by using HP1γ deficient mouse embryonic fibroblasts (MEFs). We used gene expression analysis of HP1γ deficient MEFs and validated the molecular and mechanistic consequences of HP1γ loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA immunoprecipitation (DRIP). Key findings Loss of HP1γ in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage (γH2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNA-RNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X. Significance Our results suggest an important transcriptional control by mouse HP1γ of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.

KW - Telomere

KW - HP1

KW - Chromatin

KW - DNA damage

KW - Epigenetics

KW - TERRA

UR - http://www.scopus.com/inward/record.url?scp=85168714756&partnerID=8YFLogxK

U2 - 10.1016/j.lfs.2023.122030

DO - 10.1016/j.lfs.2023.122030

M3 - Article

SN - 0024-3205

VL - 331

JO - Life Sciences

JF - Life Sciences

M1 - 122030

ER -

Mouse HP1γ regulates TRF1 expression and telomere stability

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Keywords

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