Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy

Ali Seifinejad; Mergim Ramosaj; Ling Shan; Sha Li; Marie-Laure Possovre; Corinne Pfister; Rolf Fronczek; Lee A Garrett-Sinha; David Frieser; Makoto Honda; Yoan Arribat; Dogan Grepper; Francesca Amati; Marie Picot; Andrea Agnoletto; Christian Iseli; Nicolas Chartrel; Roland Liblau; Gert J Lammers; Anne Vassalli; Mehdi Tafti

doi:10.1073/pnas.2220911120

Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy

Ali Seifinejad, Mergim Ramosaj, Ling Shan, Sha Li, Marie-Laure Possovre, Corinne Pfister, Rolf Fronczek, Lee A Garrett-Sinha, David Frieser, Makoto Honda, Yoan Arribat, Dogan Grepper, Francesca Amati, Marie Picot, Andrea Agnoletto, Christian Iseli, Nicolas Chartrel, Roland Liblau, Gert J Lammers, Anne VassalliMehdi Tafti

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Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin (PDYN) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT, PDYN, and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.

Originele taal-2	Engels
Pagina's (van-tot)	e2220911120
Tijdschrift	Proceedings of the National Academy of Sciences of the United States of America
Volume	120
Nummer van het tijdschrift	19
DOI's	https://doi.org/10.1073/pnas.2220911120
Status	Gepubliceerd - 09 mei 2023

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Seifinejad, A., Ramosaj, M., Shan, L., Li, S., Possovre, M.-L., Pfister, C., Fronczek, R., Garrett-Sinha, L. A., Frieser, D., Honda, M., Arribat, Y., Grepper, D., Amati, F., Picot, M., Agnoletto, A., Iseli, C., Chartrel, N., Liblau, R., Lammers, G. J., ... Tafti, M. (2023). Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy. Proceedings of the National Academy of Sciences of the United States of America, 120(19), e2220911120. https://doi.org/10.1073/pnas.2220911120

@article{66328ff85ca0464f9e457906ecbf509b,

title = "Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy",

abstract = "Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin (PDYN) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT, PDYN, and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.",

keywords = "Mice, Animals, Orexins/metabolism, Cataplexy/genetics, Intracellular Signaling Peptides and Proteins/metabolism, Neuropeptides/metabolism, Narcolepsy/genetics, Hypothalamus/metabolism, Epigenesis, Genetic, Corticotropin-Releasing Hormone/genetics",

author = "Ali Seifinejad and Mergim Ramosaj and Ling Shan and Sha Li and Marie-Laure Possovre and Corinne Pfister and Rolf Fronczek and Garrett-Sinha, {Lee A} and David Frieser and Makoto Honda and Yoan Arribat and Dogan Grepper and Francesca Amati and Marie Picot and Andrea Agnoletto and Christian Iseli and Nicolas Chartrel and Roland Liblau and Lammers, {Gert J} and Anne Vassalli and Mehdi Tafti",

year = "2023",

month = may,

day = "9",

doi = "10.1073/pnas.2220911120",

language = "English",

volume = "120",

pages = "e2220911120",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "19",

}

Seifinejad, A, Ramosaj, M, Shan, L, Li, S, Possovre, M-L, Pfister, C, Fronczek, R, Garrett-Sinha, LA, Frieser, D, Honda, M, Arribat, Y, Grepper, D, Amati, F, Picot, M, Agnoletto, A, Iseli, C, Chartrel, N, Liblau, R, Lammers, GJ, Vassalli, A & Tafti, M 2023, 'Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy', Proceedings of the National Academy of Sciences of the United States of America, vol. 120, nr. 19, blz. e2220911120. https://doi.org/10.1073/pnas.2220911120

Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy. / Seifinejad, Ali; Ramosaj, Mergim; Shan, Ling et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 120, Nr. 19, 09.05.2023, blz. e2220911120.

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

TY - JOUR

T1 - Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy

AU - Seifinejad, Ali

AU - Ramosaj, Mergim

AU - Shan, Ling

AU - Li, Sha

AU - Possovre, Marie-Laure

AU - Pfister, Corinne

AU - Fronczek, Rolf

AU - Garrett-Sinha, Lee A

AU - Frieser, David

AU - Honda, Makoto

AU - Arribat, Yoan

AU - Grepper, Dogan

AU - Amati, Francesca

AU - Picot, Marie

AU - Agnoletto, Andrea

AU - Iseli, Christian

AU - Chartrel, Nicolas

AU - Liblau, Roland

AU - Lammers, Gert J

AU - Vassalli, Anne

AU - Tafti, Mehdi

PY - 2023/5/9

Y1 - 2023/5/9

N2 - Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin (PDYN) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT, PDYN, and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.

AB - Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin (PDYN) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT, PDYN, and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.

KW - Mice

KW - Animals

KW - Orexins/metabolism

KW - Cataplexy/genetics

KW - Intracellular Signaling Peptides and Proteins/metabolism

KW - Neuropeptides/metabolism

KW - Narcolepsy/genetics

KW - Hypothalamus/metabolism

KW - Epigenesis, Genetic

KW - Corticotropin-Releasing Hormone/genetics

U2 - 10.1073/pnas.2220911120

DO - 10.1073/pnas.2220911120

M3 - Article

C2 - 37126681

SN - 0027-8424

VL - 120

SP - e2220911120

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 19

ER -

Epigenetic silencing of selected hypothalamic neuropeptides in narcolepsy with cataplexy

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