Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons

Ilaria Palmisano; Matt C. Danzi; Thomas H. Hutson; Luming Zhou; Eilidh McLachlan; Elisabeth Serger; Kirill Shkura; Prashant K. Srivastava; Arnau Hervera; Nick O’ Neill; Tong Liu; Hassen Dhrif; Zheng Wang; Miroslav Kubat; Stefan Wuchty; Matthias Merkenschlager; Liron Levi; Evan Elliott; John L. Bixby; Vance P. Lemmon; Simone Di Giovanni

doi:10.1038/s41593-019-0490-4

Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons

Ilaria Palmisano, Matt C. Danzi, Thomas H. Hutson, Luming Zhou, Eilidh McLachlan, Elisabeth Serger, Kirill Shkura, Prashant K. Srivastava, Arnau Hervera, Nick O’ Neill, Tong Liu, Hassen Dhrif, Zheng Wang, Miroslav Kubat, Stefan Wuchty, Matthias Merkenschlager, Liron Levi, Evan Elliott, John L. Bixby, Vance P. LemmonSimone Di Giovanni

Bar-Ilan University - Azrieli Faculty of Medicine

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

59 Scopus citations

Abstract

Axonal injury results in regenerative success or failure, depending on whether the axon lies in the peripheral or the CNS, respectively. The present study addresses whether epigenetic signatures in dorsal root ganglia discriminate between regenerative and non-regenerative axonal injury. Chromatin immunoprecipitation for the histone 3 (H3) post-translational modifications H3K9ac, H3K27ac and H3K27me3; an assay for transposase-accessible chromatin; and RNA sequencing were performed in dorsal root ganglia after sciatic nerve or dorsal column axotomy. Distinct histone acetylation and chromatin accessibility signatures correlated with gene expression after peripheral, but not central, axonal injury. DNA-footprinting analyses revealed new transcriptional regulators associated with regenerative ability. Machine-learning algorithms inferred the direction of most of the gene expression changes. Neuronal conditional deletion of the chromatin remodeler CCCTC-binding factor impaired nerve regeneration, implicating chromatin organization in the regenerative competence. Altogether, the present study offers the first epigenomic map providing insight into the transcriptional response to injury and the differential regenerative ability of sensory neurons.

Original language	English
Pages (from-to)	1913-1924
Number of pages	12
Journal	Nature Neuroscience
Volume	22
Issue number	11
DOIs	https://doi.org/10.1038/s41593-019-0490-4
State	Published - 1 Nov 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

We would like to acknowledge the start-up funds: Division of Brain Sciences, Imperial College London (S.D.G.), Wings for Life grant no. WFL-UK-07/16 (S.D.G.), Rosetrees Trust grant no. A1438 (S.D.G.), the Leverhulme Trust grant no. RPG-2015-092 (S.D.G.), ISRT (S.D.G.), the Medical Research Council grant no. R/R005311/1 (S.D.G.) and WT grant no. 099276/Z/12/Z (M.M.). The research was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (S.D.G.). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We thank C. Sibley, Imperial College London, for useful discussion and suggestions.

Funders	Funder number
Division of Brain Sciences
ISRT
Wings for Life	RPG-2015-092
Medical Research Council
National Institute for Health Research
Imperial College London
NIHR Imperial Biomedical Research Centre
Wellcome Trust Centre for Mitochondrial Research

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Palmisano, I., Danzi, M. C., Hutson, T. H., Zhou, L., McLachlan, E., Serger, E., Shkura, K., Srivastava, P. K., Hervera, A., Neill, N. O., Liu, T., Dhrif, H., Wang, Z., Kubat, M., Wuchty, S., Merkenschlager, M., Levi, L., Elliott, E., Bixby, J. L., ... Di Giovanni, S. (2019). Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons. Nature Neuroscience, 22(11), 1913-1924. https://doi.org/10.1038/s41593-019-0490-4

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abstract = "Axonal injury results in regenerative success or failure, depending on whether the axon lies in the peripheral or the CNS, respectively. The present study addresses whether epigenetic signatures in dorsal root ganglia discriminate between regenerative and non-regenerative axonal injury. Chromatin immunoprecipitation for the histone 3 (H3) post-translational modifications H3K9ac, H3K27ac and H3K27me3; an assay for transposase-accessible chromatin; and RNA sequencing were performed in dorsal root ganglia after sciatic nerve or dorsal column axotomy. Distinct histone acetylation and chromatin accessibility signatures correlated with gene expression after peripheral, but not central, axonal injury. DNA-footprinting analyses revealed new transcriptional regulators associated with regenerative ability. Machine-learning algorithms inferred the direction of most of the gene expression changes. Neuronal conditional deletion of the chromatin remodeler CCCTC-binding factor impaired nerve regeneration, implicating chromatin organization in the regenerative competence. Altogether, the present study offers the first epigenomic map providing insight into the transcriptional response to injury and the differential regenerative ability of sensory neurons.",

author = "Ilaria Palmisano and Danzi, {Matt C.} and Hutson, {Thomas H.} and Luming Zhou and Eilidh McLachlan and Elisabeth Serger and Kirill Shkura and Srivastava, {Prashant K.} and Arnau Hervera and Neill, {Nick O{\textquoteright}} and Tong Liu and Hassen Dhrif and Zheng Wang and Miroslav Kubat and Stefan Wuchty and Matthias Merkenschlager and Liron Levi and Evan Elliott and Bixby, {John L.} and Lemmon, {Vance P.} and {Di Giovanni}, Simone",

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doi = "10.1038/s41593-019-0490-4",

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Palmisano, I, Danzi, MC, Hutson, TH, Zhou, L, McLachlan, E, Serger, E, Shkura, K, Srivastava, PK, Hervera, A, Neill, NO, Liu, T, Dhrif, H, Wang, Z, Kubat, M, Wuchty, S, Merkenschlager, M, Levi, L, Elliott, E, Bixby, JL, Lemmon, VP & Di Giovanni, S 2019, 'Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons', Nature Neuroscience, vol. 22, no. 11, pp. 1913-1924. https://doi.org/10.1038/s41593-019-0490-4

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AU - Palmisano, Ilaria

AU - Danzi, Matt C.

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AU - Zhou, Luming

AU - McLachlan, Eilidh

AU - Serger, Elisabeth

AU - Shkura, Kirill

AU - Srivastava, Prashant K.

AU - Hervera, Arnau

AU - Neill, Nick O’

AU - Liu, Tong

AU - Dhrif, Hassen

AU - Wang, Zheng

AU - Kubat, Miroslav

AU - Wuchty, Stefan

AU - Merkenschlager, Matthias

AU - Levi, Liron

AU - Elliott, Evan

AU - Bixby, John L.

AU - Lemmon, Vance P.

AU - Di Giovanni, Simone

PY - 2019/11/1

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N2 - Axonal injury results in regenerative success or failure, depending on whether the axon lies in the peripheral or the CNS, respectively. The present study addresses whether epigenetic signatures in dorsal root ganglia discriminate between regenerative and non-regenerative axonal injury. Chromatin immunoprecipitation for the histone 3 (H3) post-translational modifications H3K9ac, H3K27ac and H3K27me3; an assay for transposase-accessible chromatin; and RNA sequencing were performed in dorsal root ganglia after sciatic nerve or dorsal column axotomy. Distinct histone acetylation and chromatin accessibility signatures correlated with gene expression after peripheral, but not central, axonal injury. DNA-footprinting analyses revealed new transcriptional regulators associated with regenerative ability. Machine-learning algorithms inferred the direction of most of the gene expression changes. Neuronal conditional deletion of the chromatin remodeler CCCTC-binding factor impaired nerve regeneration, implicating chromatin organization in the regenerative competence. Altogether, the present study offers the first epigenomic map providing insight into the transcriptional response to injury and the differential regenerative ability of sensory neurons.

AB - Axonal injury results in regenerative success or failure, depending on whether the axon lies in the peripheral or the CNS, respectively. The present study addresses whether epigenetic signatures in dorsal root ganglia discriminate between regenerative and non-regenerative axonal injury. Chromatin immunoprecipitation for the histone 3 (H3) post-translational modifications H3K9ac, H3K27ac and H3K27me3; an assay for transposase-accessible chromatin; and RNA sequencing were performed in dorsal root ganglia after sciatic nerve or dorsal column axotomy. Distinct histone acetylation and chromatin accessibility signatures correlated with gene expression after peripheral, but not central, axonal injury. DNA-footprinting analyses revealed new transcriptional regulators associated with regenerative ability. Machine-learning algorithms inferred the direction of most of the gene expression changes. Neuronal conditional deletion of the chromatin remodeler CCCTC-binding factor impaired nerve regeneration, implicating chromatin organization in the regenerative competence. Altogether, the present study offers the first epigenomic map providing insight into the transcriptional response to injury and the differential regenerative ability of sensory neurons.

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Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons

Abstract

Bibliographical note

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