Maternal expression and early induction of histone gene transcription factor Hinfp sustains development in pre-implantation embryos.
Fidelity of histone gene expression is important for normal cell growth and differentiation that is stringently controlled during development but is compromised during tumorigenesis. Efficient production of histones for packaging newly replicated DNA is particularly important for proper cell division and epigenetic control during the initial pre-implantation stages of embryonic development. Here, we addressed the unresolved question of when the machinery for histone gene transcription is activated in the developing zygote to accommodate temporal demands for histone gene expression. We examined induction of Histone Nuclear Factor P (HINFP), the only known transcription factor required for histone H4 gene expression, that binds directly to a unique H4 promoter-specific element to regulate histone H4 transcription. We show that Hinfp gene transcripts are stored in oocytes and maternally transmitted to the zygote. Transcripts from the paternal Hinfp gene, which reflect induction of zygotic gene expression, are apparent at the 4- to 8-cell stage, when most maternal mRNA pools are depleted. Loss of Hinfp expression due to gene ablation reduces cell numbers in E3.5 stage embryos and compromises implantation. Reduced cell proliferation is attributable to severe reduction in histone mRNA levels accompanied by reduced cell survival and genomic damage as measured by cleaved Caspase 3 and phospho-H2AX staining, respectively. We conclude that transmission of maternal Hinfp transcripts and zygotic activation of the Hinfp gene together are necessary to control H4 gene expression in early pre-implantation embryos in order to support normal embryonic development.
Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405, USA; Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. Electronic address: prachi.ghule@uvm.edu.
Prachi N
PN
Ghule
Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. Electronic address: ronglin.xie@yahoo.com.
Rong-Lin
RL
Xie
Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. Electronic address: jfaucette@gmail.com.
Jennifer L
JL
Colby
Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. Electronic address: jaime.rivera@umassmed.edu.
Jaime A
JA
Rivera-Pérez
Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. Electronic address: stephen.jones@umassmed.edu.
Stephen N
SN
Jones
Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405, USA; Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. Electronic address: jane.lian@uvm.edu.
Jane B
JB
Lian
Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405, USA; Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. Electronic address: janet.stein@uvm.edu.
Janet L
JL
Stein
Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA; Departments of Orthopedic Surgery and Biochemistry & Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address: vanwijnen.andre@mayo.edu.
Andre J
AJ
van Wijnen
Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405, USA; Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. Electronic address: gary.stein@uvm.edu.
Gary S
GS
Stein
D000818:Animals; D001755:Blastocyst / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D010064:Embryo Implantation / Q000502:physiology; D047108:Embryonic Development / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D006657:Histones / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D023121:RNA, Messenger, Stored / Q000235:genetics*; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015053:Zygote / Q000378:metabolism*
D053148:Caspase 3; D006657:Histones; D012333:RNA, Messenger; D023121:RNA, Messenger, Stored; D012097:Repressor Proteins; C524750:HiNF-P protein, mouse; C505409:Casp3 protein, mouse; C475961:gamma-H2AX protein, mouse
HLB; Hinfp; Histone H4; Mouse embryonic development; NPAT