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Nucleic Acids Res. 2019 Mar 29. pii: gkz195. doi: 10.1093/nar/gkz195. [Epub ahead of print]

Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment.

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Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Spain.
Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), ISPA-Hospital Universitario Central de Asturias HUCA, Universidad de Oviedo, Oviedo, Spain.
Josep Carreras Leukemia Research Institute and Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red en Cáncer (CIBER-ONC), Barcelona, Spain.
Hematology Research Group, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, 46026, Spain.
Translational Immunology Laboratory, Instituto de Investigación Sanitarias del Principado de Asturias (ISPA), Immunology Department, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
Servicio de Hematología, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
Service of Molecular Oncology, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
Department of Morphology and Cellular Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.
Otorhinolaryngology Service, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, CIBERONC, Oviedo, Spain.
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
Hospital Universitario Central de Asturias (HUCA), Instituto Nacional de Silicosis (INS), Área del Pulmón, Facultad de Medicina, Universidad de Oviedo, Avenida Roma s/n, Oviedo, Asturias 33011, Spain.
Hospital Universitario Central de Asturias (HUCA), Gastroenterology Service, Facultad de Medicina, Universidad de Oviedo, Avenida de Roma s/n, Oviedo, Asturias 33011, Spain.
Fundación para la Investigación Biosanitaria de Asturias (FINBA). Instituto de Investigación Sanitaria del Principado de Asturias (ISPA). Avenida de Roma s/n, 33011 Oviedo. Asturias. España.
Cytometry Service, Servicios Científico-Técnicos (SCTs). Universidad de Oviedo, Oviedo, Spain.
Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, 28049 Madrid, Spain.
Institute of Cellular Medicine, Newcastle University, UK.
Hemorheology and Haemostasis Unit, Service of Clinical Pathology, La Fe University Hospital, Valencia, Spain.
Dermatology Service, Quirón Clinic, Valencia, Spain.
George Washington University Cancer Center, Department of Biochemistry and Molecular Medicine, George Washington University, Washington, DC 20037, USA.
Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Via de l'Hospitalet, 199-203, 08907- L'Hospitalet de Llobregat, Barcelona, Spain.
Plant Physiology Lab, Department of Organisms and Systems Biology, Faculty of Biology, University of Oviedo, Oviedo, Asturias, Spain.
Bioinformatics Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro, 3. 28029 Madrid, Spain.
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Institute of Biochemistry, Genetics and Microbiology, University of Regensburg, 93053 Regensburg, Germany.


Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.


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