Spatiotemporal higher-order chromatin landscape of human histone gene clusters at histone locus bodies during the cell cycle in breast cancer progression

Prachi N Ghule; Joseph R Boyd; Fleur Kabala; Andrew J Fritz; Nicole A Bouffard; Cong Gao; Kathleen Bright; Jill Macfarlane; David J Seward; Gianluca Pegoraro; Tom Misteli; Jane B Lian; Seth Frietze; Janet L Stein; Andre J van Wijnen; Gary S Stein

doi:10.1016/j.gene.2023.147441

Spatiotemporal higher-order chromatin landscape of human histone gene clusters at histone locus bodies during the cell cycle in breast cancer progression

Gene. 2023 Jul 1:872:147441. doi: 10.1016/j.gene.2023.147441. Epub 2023 Apr 23.

Authors

Prachi N Ghule¹, Joseph R Boyd², Fleur Kabala³, Andrew J Fritz⁴, Nicole A Bouffard⁵, Cong Gao⁶, Kathleen Bright⁶, Jill Macfarlane³, David J Seward⁷, Gianluca Pegoraro⁸, Tom Misteli⁹, Jane B Lian¹⁰, Seth Frietze¹¹, Janet L Stein¹², Andre J van Wijnen¹³, Gary S Stein¹⁴

Affiliations

¹ Department of Biochemistry and University of Vermont Cancer Center, Larner College of Medicine at the University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: prachi.ghule@med.uvm.edu.
² Department of Biomedical and Health Sciences and University of Vermont Cancer Center, College of Nursing and Health Sciences, University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: joseph.boyd@med.uvm.edu.
³ Department of Biochemistry and University of Vermont Cancer Center, Larner College of Medicine at the University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA.
⁴ Department of Biochemistry and University of Vermont Cancer Center, Larner College of Medicine at the University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: andrew.fritz@med.uvm.edu.
⁵ Microscopy Imaging Center, Center for Biomedical Shared Resources at the University of Vermont, 150 Firestone Building, 149 Beaumont Ave, Burlington, VT 05405, USA.
⁶ Department of Biomedical and Health Sciences and University of Vermont Cancer Center, College of Nursing and Health Sciences, University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA.
⁷ Department of Pathology and University of Vermont Cancer Center, Larner College of Medicine at the University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: david.seward@uvmhealth.org.
⁸ High-Throughput Imaging Facility (HiTIF), Center for Cancer Research (CCR), National Cancer Institute, NIH, Bethesda, MD 20892, USA.
⁹ Cell Biology of Genomes, Center for Cancer Research (CCR), National Cancer Institute, NIH, Bethesda, MD 20892, USA.
¹⁰ Department of Biochemistry and University of Vermont Cancer Center, Larner College of Medicine at the University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: jane.lian@med.uvm.edu.
¹¹ Department of Biomedical and Health Sciences and University of Vermont Cancer Center, College of Nursing and Health Sciences, University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: seth.frietze@med.uvm.edu.
¹² Department of Biochemistry and University of Vermont Cancer Center, Larner College of Medicine at the University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: janet.stein@med.uvm.edu.
¹³ Department of Biochemistry and University of Vermont Cancer Center, Larner College of Medicine at the University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: andre.vanwijnen@uvm.edu.
¹⁴ Department of Biochemistry and University of Vermont Cancer Center, Larner College of Medicine at the University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: gary.stein@uvm.edu.

PMID: 37094694
PMCID: PMC10370284 (available on 2024-07-01)
DOI: 10.1016/j.gene.2023.147441

Abstract

Human Histone Locus Bodies (HLBs) are nuclear subdomains comprised of clustered histone genes that are coordinately regulated throughout the cell cycle. We addressed temporal-spatial higher-order genome organization for time-dependent chromatin remodeling at HLBs that supports control of cell proliferation. Proximity distances of specific genomic contacts within histone gene clusters exhibit subtle changes during the G1 phase in MCF10 breast cancer progression model cell lines. This approach directly demonstrates that the two principal histone gene regulatory proteins, HINFP (H4 gene regulator) and NPAT, localize at chromatin loop anchor-points, denoted by CTCF binding, supporting the stringent requirement for histone biosynthesis to package newly replicated DNA as chromatin. We identified a novel enhancer region located ∼ 2 MB distal to histone gene sub-clusters on chromosome 6 that consistently makes genomic contacts with HLB chromatin and is bound by NPAT. During G1 progression the first DNA loops form between one of three histone gene sub-clusters bound by HINFP and the distal enhancer region. Our findings are consistent with a model that the HINFP/NPAT complex controls the formation and dynamic remodeling of higher-order genomic organization of histone gene clusters at HLBs in early to late G1 phase to support transcription of histone mRNAs in S phase.

Keywords: HINFP; HiC; Histone genes; Histone locus body (HLB); NPAT.

MeSH terms

Breast Neoplasms* / genetics
Cell Cycle / genetics
Cell Cycle Proteins / genetics
Chromatin / genetics
Female
Histones* / genetics
Histones* / metabolism
Humans
Multigene Family
Nuclear Bodies

Substances

Histones
Chromatin
Cell Cycle Proteins

Abstract

MeSH terms

Substances

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