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Article ; Online: Wearable full-body motion tracking of activities of daily living predicts disease trajectory in Duchenne muscular dystrophy.

Ricotti, Valeria / Kadirvelu, Balasundaram / Selby, Victoria / Festenstein, Richard / Mercuri, Eugenio / Voit, Thomas / Faisal, A Aldo

Nature medicine

2023 Volume 29, Issue 1, Page(s) 95–103

Abstract: Artificial intelligence has the potential to revolutionize healthcare, yet clinical trials in neurological diseases continue to rely on subjective, semiquantitative and motivation-dependent endpoints for drug development. To overcome this limitation, we ... ...

Abstract	Artificial intelligence has the potential to revolutionize healthcare, yet clinical trials in neurological diseases continue to rely on subjective, semiquantitative and motivation-dependent endpoints for drug development. To overcome this limitation, we collected a digital readout of whole-body movement behavior of patients with Duchenne muscular dystrophy (DMD) (n = 21) and age-matched controls (n = 17). Movement behavior was assessed while the participant engaged in everyday activities using a 17-sensor bodysuit during three clinical visits over the course of 12 months. We first defined new movement behavioral fingerprints capable of distinguishing DMD from controls. Then, we used machine learning algorithms that combined the behavioral fingerprints to make cross-sectional and longitudinal disease course predictions, which outperformed predictions derived from currently used clinical assessments. Finally, using Bayesian optimization, we constructed a behavioral biomarker, termed the KineDMD ethomic biomarker, which is derived from daily-life behavioral data and whose value progresses with age in an S-shaped sigmoid curve form. The biomarker developed in this study, derived from digital readouts of daily-life movement behavior, can predict disease progression in patients with muscular dystrophy and can potentially track the response to therapy.
MeSH term(s)	Humans ; Muscular Dystrophy, Duchenne/drug therapy ; Activities of Daily Living ; Cross-Sectional Studies ; Artificial Intelligence ; Bayes Theorem ; Biomarkers ; Wearable Electronic Devices
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-022-02045-1
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Article ; Online: Mouse HP1γ regulates TRF1 expression and telomere stability.

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

Life sciences

2023 Volume 331, Page(s) 122030

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) ...

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.
MeSH term(s)	Animals ; Humans ; Mice ; Chromatin ; DNA ; Fibroblasts/metabolism ; RNA/genetics ; RNA/metabolism ; Telomere/genetics ; Telomere/metabolism ; Transcription Factors/genetics ; Telomeric Repeat Binding Protein 1/metabolism
Chemical Substances	Chromatin ; DNA (9007-49-2) ; RNA (63231-63-0) ; Transcription Factors ; Cbx3 protein, mouse ; Telomeric Repeat Binding Protein 1
Language	English
Publishing date	2023-08-18
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2023.122030
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Article: Epigenetics and Triplet-Repeat Neurological Diseases.

Nageshwaran, Sathiji / Festenstein, Richard

Frontiers in neurology

2015 Volume 6, Page(s) 262

Abstract: The term "junk DNA" has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. ... ...

Abstract	The term "junk DNA" has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. Repetitive regions are frequently heterochromatinized resulting in silencing of intrinsic and nearby genes. However, this is not a uniform rule, with several genes known to require such an environment to permit transcription. Repetitive regions frequently exist as dinucleotide, trinucleotide, and tetranucleotide repeats. The association between repetitive regions and disease was emphasized following the discovery of abnormal trinucleotide repeats underlying spinal and bulbar muscular atrophy (Kennedy's disease) and fragile X syndrome of mental retardation (FRAXA) in 1991. In this review, we provide a brief overview of epigenetic mechanisms and then focus on several diseases caused by DNA triplet-repeat expansions, which exhibit diverse epigenetic effects. It is clear that the emerging field of epigenetics is already generating novel potential therapeutic avenues for this group of largely incurable diseases.
Language	English
Publishing date	2015-12-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2015.00262
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Article: Breaking the silence in Friedreich's ataxia.

Festenstein, Richard

Nature chemical biology

2006 Volume 2, Issue 10, Page(s) 512–513

MeSH term(s)	Cell Line ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Friedreich Ataxia/drug therapy ; Friedreich Ataxia/genetics ; Gene Expression Regulation/drug effects ; Gene Silencing/drug effects ; Heterochromatin/drug effects ; Heterochromatin/genetics ; Histone Deacetylase Inhibitors ; Humans ; Molecular Structure ; Transcription, Genetic/drug effects
Chemical Substances	Enzyme Inhibitors ; Heterochromatin ; Histone Deacetylase Inhibitors
Language	English
Publishing date	2006-09-18
Publishing country	United States
Document type	Comment ; News
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/nchembio1006-512
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Zs.A 6251: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: A wearable motion capture suit and machine learning predict disease progression in Friedreich's ataxia.

Kadirvelu, Balasundaram / Gavriel, Constantinos / Nageshwaran, Sathiji / Chan, Jackson Ping Kei / Nethisinghe, Suran / Athanasopoulos, Stavros / Ricotti, Valeria / Voit, Thomas / Giunti, Paola / Festenstein, Richard / Faisal, A Aldo

Nature medicine

2023 Volume 29, Issue 1, Page(s) 86–94

Abstract: Friedreich's ataxia (FA) is caused by a variant of the Frataxin (FXN) gene, leading to its downregulation and progressively impaired cardiac and neurological function. Current gold-standard clinical scales use simplistic behavioral assessments, which ... ...

Abstract	Friedreich's ataxia (FA) is caused by a variant of the Frataxin (FXN) gene, leading to its downregulation and progressively impaired cardiac and neurological function. Current gold-standard clinical scales use simplistic behavioral assessments, which require 18- to 24-month-long trials to determine if therapies are beneficial. Here we captured full-body movement kinematics from patients with wearable sensors, enabling us to define digital behavioral features based on the data from nine FA patients (six females and three males) and nine age- and sex-matched controls, who performed the 8-m walk (8-MW) test and 9-hole peg test (9 HPT). We used machine learning to combine these features to longitudinally predict the clinical scores of the FA patients, and compared these with two standard clinical assessments, Spinocerebellar Ataxia Functional Index (SCAFI) and Scale for the Assessment and Rating of Ataxia (SARA). The digital behavioral features enabled longitudinal predictions of personal SARA and SCAFI scores 9 months into the future and were 1.7 and 4 times more precise than longitudinal predictions using only SARA and SCAFI scores, respectively. Unlike the two clinical scales, the digital behavioral features accurately predicted FXN gene expression levels for each FA patient in a cross-sectional manner. Our work demonstrates how data-derived wearable biomarkers can track personal disease trajectories and indicates the potential of such biomarkers for substantially reducing the duration or size of clinical trials testing disease-modifying therapies and for enabling behavioral transcriptomics.
MeSH term(s)	Male ; Female ; Humans ; Friedreich Ataxia/diagnosis ; Friedreich Ataxia/genetics ; Cross-Sectional Studies ; Motion Capture ; Spinocerebellar Ataxias ; Disease Progression ; Machine Learning ; Biomarkers ; Wearable Electronic Devices
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-022-02159-6
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Mouse HP1γ regulates TRF1 expression and telomere stability

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

Life Sciences. 2023 Oct., v. 331 p.122030-

2023

Abstract: 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) ... ...

Abstract	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. 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). 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. 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	DNA damage ; cohesion ; epigenetics ; fibroblasts ; fish ; fluorescent antibody technique ; gene expression ; genes ; heterochromatin ; humans ; mice ; precipitin tests ; sexual dimorphism ; telomeres ; transcription (genetics) ; Telomere ; HP1 ; Chromatin ; TERRA
Language	English
Dates of publication	2023-10
Publishing place	Elsevier Inc.
Document type	Article ; Online
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2023.122030
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Article ; Online: Context is everything: activators can also repress.

Festenstein, Richard / Chan, Jackson P K

Nature structural & molecular biology

2012 Volume 19, Issue 10, Page(s) 973–975

Abstract: Maintenance of genome integrity, cell division and gene expression have all been shown to be regulated by the condensation of DNA into heterochromatin. In a study published in this issue, Bulut-Karslioglu et al. reveal a new heterochromatin function for ... ...

Abstract	Maintenance of genome integrity, cell division and gene expression have all been shown to be regulated by the condensation of DNA into heterochromatin. In a study published in this issue, Bulut-Karslioglu et al. reveal a new heterochromatin function for transcription factors in a mammalian system. They show that instead of activating gene expression, in the context of heterochromatic repeats, specific transcription factors are necessary for the maintenance of transcriptional repression and heterochromatin.
MeSH term(s)	Animals ; Heterochromatin/metabolism ; PAX3 Transcription Factor ; PAX9 Transcription Factor ; Paired Box Transcription Factors/metabolism
Chemical Substances	Heterochromatin ; PAX3 Transcription Factor ; PAX9 Transcription Factor ; Paired Box Transcription Factors ; Pax9 protein, mouse ; Pax3 protein, mouse (138016-91-8)
Language	English
Publishing date	2012-10-01
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/nsmb.2401
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Article: Epigenetic regulation of autosomal gene expression by sex chromosomes.

Wijchers, Patrick J / Festenstein, Richard J

Trends in genetics : TIG

2011 Volume 27, Issue 4, Page(s) 132–140

Abstract: Males and females display differences in physiology, behaviour and susceptibility to many diseases. Genome-wide transcription profiling studies have uncovered large-scale sex differences in autosomal gene expression in somatic tissues that are thought to ...

Abstract	Males and females display differences in physiology, behaviour and susceptibility to many diseases. Genome-wide transcription profiling studies have uncovered large-scale sex differences in autosomal gene expression in somatic tissues that are thought to underlie such 'sexual dimorphisms'. Because males and females differ genetically mainly in their sex chromosome complement, most sex differences can be traced back to the X and Y chromosomes. Although sex hormones are usually considered the main architects of sexual dimorphisms, recent studies have demonstrated that sex chromosomes can also induce sex differences in somatic gene expression in the absence of hormonal differences. The recent discovery of epigenetic sex differences that are not hormone-induced brings us closer to understanding differences in autosomal gene expression. In this review, we discuss the insights gained from these findings and the mechanisms by which X and Y chromosomes might induce epigenetic sex differences.
MeSH term(s)	Aneuploidy ; Animals ; Epigenesis, Genetic ; Humans ; Sex Characteristics ; Sex Chromosomes ; Transcription, Genetic
Language	English
Publishing date	2011-02-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	619240-3
ISSN	1362-4555 ; 0168-9525 ; 0168-9479
ISSN (online)	1362-4555
ISSN	0168-9525 ; 0168-9479
DOI	10.1016/j.tig.2011.01.004
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Article ; Online: High-Throughput Production of Proteins in E. coli for Structural Studies.

Black, Charikleia / Barker, John J / Hitchman, Richard B / Kwong, Hok Sau / Festenstein, Sam / Acton, Thomas B

Methods in molecular biology (Clifton, N.J.)

2017 Volume 1586, Page(s) 359–371

Abstract: We have developed a standardized and efficient workflow for high-throughput (HT) protein expression in E. coli and parallel purification which can be tailored to the downstream application of the target proteins. It includes a one-step purification for ... ...

Abstract	We have developed a standardized and efficient workflow for high-throughput (HT) protein expression in E. coli and parallel purification which can be tailored to the downstream application of the target proteins. It includes a one-step purification for the purposes of functional assays and a two-step protocol for crystallographic studies, with the option of on-column tag removal.
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-6887-9_24
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Article ; Online: Gene regulation and epigenetics in Friedreich's ataxia.

Yandim, Cihangir / Natisvili, Theona / Festenstein, Richard

Journal of neurochemistry

2013 Volume 126 Suppl 1, Page(s) 21–42

Abstract: This is an exciting time in the study of Friedreich's ataxia. Over the last 10 years much progress has been made in uncovering the mechanisms, whereby the Frataxin gene is silenced by (GAA)n repeat expansions and several of the findings are now ripe for ... ...

Abstract	This is an exciting time in the study of Friedreich's ataxia. Over the last 10 years much progress has been made in uncovering the mechanisms, whereby the Frataxin gene is silenced by (GAA)n repeat expansions and several of the findings are now ripe for testing in the clinic. The discovery that the Frataxin gene is heterochromatinised and that this can be antagonised in vivo has led to the tantalizing possibility that the disease might be amenable to a more radical therapeutic approach involving epigenetic modifiers. Here, we set out to review progress in the understanding of the fundamental mechanisms whereby genes are regulated at this level and how these findings have been applied to achieve a deeper understanding of the dysregulation that occurs as the primary genetic lesion in Friedreich's ataxia.
MeSH term(s)	DNA Methylation ; DNA Repeat Expansion ; DNA, Antisense/genetics ; Epigenesis, Genetic/genetics ; Friedreich Ataxia/genetics ; Gene Expression Regulation/genetics ; Histones/metabolism ; Humans ; Iron-Binding Proteins/genetics ; RNA Interference ; Transcription, Genetic/genetics ; Frataxin
Chemical Substances	DNA, Antisense ; Histones ; Iron-Binding Proteins
Language	English
Publishing date	2013-07-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.12254
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