Butyrate modifies epigenetic and immune pathways in peripheral mononuclear cells from children with neurodevelopmental disorders associated with chromatin dysregulation

Jessica P Hayes¹, Velda X Han², Brooke A Keating¹, Hiroya Nishida¹, Erica Tsang¹, Xianzhong Lau³, Ruwani Dissanayake⁴, Nader Aryamanesh⁵, Wendy Gold¹, Melanie Wong⁶, Carolyn Ellaway⁷, Brian S Gloss⁸, Shekeeb S Mohammad⁹, Markus J Hofer¹⁰, Peter Valtchev¹¹, Shrujna Patel¹², Russell C Dale¹³

Affiliations

¹ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
² Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³ Australian Genome Research Facility Ltd, Melbourne, VIC, Australia.
⁴ Australian Genome Research Facility Ltd, Westmead, NSW, Australia.
⁵ Bioinformatics Group, Children's Medical Research Institute, University of Sydney, Westmead, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁶ The Children's Hospital at Westmead, Department of Allergy and Immunology, Australia.
⁷ The Children's Hospital at Westmead, Genetic Metabolic Disorders Service, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁸ Westmead Research Hub, Westmead Institute for Medical Research, Westmead, NSW, Australia.
⁹ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
¹⁰ School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
¹¹ School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, NSW, Australia; School of Chemical and Biomolecular Engineering, Faculty of Engineering, The University of Sydney, Sydney, NSW, Australia.
¹² Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; The University of Sydney, School of Medical Sciences and Discipline of Child and Adolescent Health, Faculty of Medicine and Health, Sydney, NSW, Australia.
¹³ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; The University of Sydney, School of Medical Sciences and Discipline of Child and Adolescent Health, Faculty of Medicine and Health, Sydney, NSW, Australia. Electronic address: russell.dale@sydney.edu.au.

PMID: 41260988
DOI: 10.1016/j.neurot.2025.e00792

Free article

Butyrate modifies epigenetic and immune pathways in peripheral mononuclear cells from children with neurodevelopmental disorders associated with chromatin dysregulation

Jessica P Hayes et al. Neurotherapeutics. 2025.

Free article

. 2025 Nov 18:e00792.

doi: 10.1016/j.neurot.2025.e00792. Online ahead of print.

Authors

Affiliations

¹ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
² Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³ Australian Genome Research Facility Ltd, Melbourne, VIC, Australia.
⁴ Australian Genome Research Facility Ltd, Westmead, NSW, Australia.
⁵ Bioinformatics Group, Children's Medical Research Institute, University of Sydney, Westmead, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁶ The Children's Hospital at Westmead, Department of Allergy and Immunology, Australia.
⁷ The Children's Hospital at Westmead, Genetic Metabolic Disorders Service, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁸ Westmead Research Hub, Westmead Institute for Medical Research, Westmead, NSW, Australia.
⁹ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
¹⁰ School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
¹¹ School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, NSW, Australia; School of Chemical and Biomolecular Engineering, Faculty of Engineering, The University of Sydney, Sydney, NSW, Australia.
¹² Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; The University of Sydney, School of Medical Sciences and Discipline of Child and Adolescent Health, Faculty of Medicine and Health, Sydney, NSW, Australia.
¹³ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; The University of Sydney, School of Medical Sciences and Discipline of Child and Adolescent Health, Faculty of Medicine and Health, Sydney, NSW, Australia. Electronic address: russell.dale@sydney.edu.au.

PMID: 41260988
DOI: 10.1016/j.neurot.2025.e00792

Abstract

Pathogenic DNA variants in chromatin-related genes constitute an important minority of neurodevelopmental disorders (NDDs). Epigenetic mechanisms, including chromatin regulation driven by genetic or environmental factors, are increasingly recognised as key contributors to pathogenesis of diverse NDDs. We hypothesise that therapeutic strategies targeting chromatin dysregulation, such as histone deacetylase inhibition with butyrate, may be a potential disease modifying therapy for NDDs. We first performed peripheral blood bulk RNA sequencing (RNA-seq) to explore baseline gene regulation in children with chromatin-related NDDs (Kabuki syndrome (KMT2D, n = 4), CHARGE syndrome (CHD7, n = 2), and Rett syndrome (MECP2, n = 5), and children with NDDs but without a monogenic diagnosis (non-monogenic, n = 8), compared with sex-matched healthy controls (total n = 21). Next, to explore the effects of butyrate, single-cell RNA sequencing (scRNA-seq) was performed on 101,539 peripheral immune cells from four selected patients (one per condition) and two controls, before and after butyrate treatment. At baseline, dysregulation of ribosomal and immune pathways was seen in all four NDD cohorts (KMT2D, CHD7, MECP2, non-monogenic) compared to controls. Butyrate largely reversed these pathways, normalising ribosomal and immune pathways in patient and control cells. Butyrate induced up-regulation of ribosome, GTPase, cytoskeletal, mitochondrial pathways, and down-regulation of epigenetic and immune pathways. In conclusion, we identified a common ribosomal-immune RNA signature in chromatin-related NDDs, and a similar signature in non-monogenic NDDs. We showed that butyrate modulates epigenetic and immune gene networks in monogenic and non-monogenic NDDs, positioning butyrate as a promising therapeutic modulator across diverse NDDs.

Keywords: Butyrate; Chromatin; Epigenetics; Histone deacetylase inhibition; Neurodevelopmental disorders; Neuroregression.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Russell Dale reports financial support was provided by National Health and Medical Research Council. Russell Dale reports financial support was provided by Petre Foundation. Russell Dale reports financial support was provided by National Foundation for Medical Research and Innovation. Russell Dale reports financial support was provided by Avant Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Butyrate modifies epigenetic and immune pathways in peripheral mononuclear cells from children with neurodevelopmental disorders associated with chromatin dysregulation

Affiliations

Butyrate modifies epigenetic and immune pathways in peripheral mononuclear cells from children with neurodevelopmental disorders associated with chromatin dysregulation

Authors

Affiliations

Abstract

Conflict of interest statement

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