Functional coupling of transcription factor HiNF-P and histone H4 gene expression during pre- and post-natal mouse development

Abstract

Transcription factor Histone Nuclear Factor P (HiNF-P; gene symbol Hinfp) mediates cell cycle control of histone H4 gene expression to support the packaging of newly replicated DNA as chromatin. The HiNF-P/p220NPAT complex controls multiple H4 genes in established human cell lines and is critical for cell proliferation. The mouse HinfpLacZ null allele causes early embryonic lethality due to a blastocyst defect. However, neither Hinfp function nor its temporal expression relative to histone H4 genes during fetal development has been explored. Here, we establish that expression of Hinfp is biologically coupled with expression of twelve functional mouse H4 genes during pre- and post-natal tissue-development. Both Hinfp and H4 genes are robustly expressed at multiple embryonic (E) days (from E5.5 to E15.5), coincident with ubiquitous LacZ staining driven by the Hinfp promoter. Five highly expressed mouse H4 genes (Hist1h4d, Histh4f, Hist1h4m and Hist2h4) account for >90% of total histone H4 mRNA throughout development. Post-natal expression of H4 genes in mice is most evident in lung, spleen, thymus and intestine, and with few exceptions (e.g., adult liver) correlates with Hinfp gene expression. Histone H4 gene expression decreases but Hinfp levels remain constitutive upon cell growth inhibition in culture. The in vivo co-expression of Hinfp and histone H4 genes is consistent with the biological function of Hinfp as a principal transcriptional regulator of histone H4 gene expression during mouse development.

Maternal expression and early induction of histone gene transcription factor Hinfp sustains development in pre-implantation embryos

“…Based on the combined results from present and previous studies (Ghule et al, 2014; Liu et al, 2011; Xie et al, 2009), the embryonic phenotype of Hinfp deficiency can now be depicted as follows. The first noticeable defect in Hinfp null embryos is a delay in the development of blastocysts (E3.5) which exhibit a reduced cell number.…”

“…Embryos were collected at E3.5 (blastocyst) by uterine flush, at E4.5 stage by uterine flush as well as surgical removal from uterus and at E2.5, E2 and E1.5 by flushing the oviduct with M2 medium (Invitrogen) (Nagy et al, 2003). Expression of the lacZ reporter gene under control of the endogenous Hinfp promoter was examined in embryos using β-galactosidase staining (Liu et al, 2011). …”

“…Hinfp expression correlates with histone H4 gene expression throughout fetal mouse development (Liu et al, 2011). Complete genomic ablation of Hinfp in mice causes embryonic lethality before E6.5, while mice heterozygous for Hinfp are viable and survive to adulthood (Xie et al, 2009).…”

p53 checkpoint ablation exacerbates the phenotype of Hinfp dependent histone H4 deficiency

“…[9][10][11][19][20][21] Our recent findings indicated that Hinfp-mediated control of histone H4 gene expression during S phase is essential for cell growth and proliferation. [22][23][24] Complete ablation of Hinfp in mice causes early embryonic lethality between embryonic day (E) 3.5 and E6.5. In vitro cultures of Hinfp-null embryos at E3.5 exhibit abnormal growth and proliferation.…”

Cell cycle gene expression networks discovered using systems biology: Significance in carcinogenesis

“…An important mechanism that serves to influence the function of such cell cycle complexes is the relative expression of various cell cycle proteins. Protein stoichiometry control involving changes in the expression of groups of proteins by as little as twofold have been reported to influence cellular behavior by modifying the normal stoichiometry of protein complex subunits, such as those required for competency to proliferate (Ford and Pardee, ; Blagosklonny and Pardee, ; Pardee, ; Pardee et al, ; Pardee and Qiao, ), initiation of S‐Phase and histone gene expression (Vaughan et al, , ; Aziz et al, ; Ghule et al, , 2014; Miele et al, ; Stein et al, ; Mitra et al, ; Xie et al, , 2011; Liu et al, ), cell cycle progression and mitosis (Torres et al, ; Hanahan and Weinberg, ; Bertoli et al, ; Ferrell, ; Herrup, ; Lim and Kaldis, ; Williams and Fuchs, ; Yang and Ferrell, ; Zaidi et al, ; London and Biggins, ).…”