Regulation of DNA replication-coupled histone gene expression

Abstract

The expression of core histone genes is cell cycle regulated. Large amounts of histones are required to restore duplicated chromatin during S phase when DNA replication occurs. Over-expression and excess accumulation of histones outside S phase are toxic to cells and therefore cells need to restrict histone expression to S phase. Misregulation of histone gene expression leads to defects in cell cycle progression, genome stability, DNA damage response and transcriptional regulation. Here, we discussed the factors involved in histone gene regulation as well as the underlying mechanism. Understanding the histone regulation mechanism will shed lights on elucidating the side effects of certain cancer chemotherapeutic drugs and developing potential biomarkers for tumor cells.

Keywords: DNA replication; cell cycle; histone gene transcription.

Figure 1. Histone gene structure in yeast and mammals

(A) Structure of yeast canonical histone genes. All four core histone genes contain UAS elements. HTA2 and HTB2 have no NEG region. (B) Structure of yeast histone variants H2AZ and CenH3. (C) Structure of mammalian histone genes H2B and H4. Figures were adapted from [14].

Figure 2. Model for histone gene regulation in budding yeast

(A) Repressed histone gene transcription in G1 phase. HIR is recruited to the NEG region by a yet unknown factor(s), which then recruits Asf1, H3-H4 tetramers and Rtt106. RSC is recruited by Rtt106 and functions along with HIR/Asf1/Rtt106 to form a repressive chromatin structure to occlude the basal transcription machinery. APC/C^cdh1 degrades Spt21 at G1 phase to ensure that histone gene expression is tightly restricted to S phase. (B) Activated histone gene transcription in late G1 and S phase. Spt10 and Spt21 are recruited to UAS region to enhance the binding of Gcn5 and other HATs to acetylate histones in histone promoters. Rtt109-dependent incorporation of H3 acetylated at K56 (H3K56ac) enables recruitment of SWI/SNF and probably dissociation of RSC complex, which removes nucleosomes in the promoter, facilitating the recruitment of RNA polymerase II. S phase forms of CDK1 (S-CDK) then phosphorylate Yta7 causing its eviction from promoters, which is important for efficient promoter escape and transcription elongation by RNA polymerase II. (C) Negative feedback repressed histone gene transcription at the end of S phase. At the end of DNA replication, the chaperones are fully charged with histones and inhibit gene transcription. Figures were adapted from [5]. RSC, remodels structure of chromatin;RNAPII, RNA polymerase II; S-CDK, S phase forms of CDK1.

Figure 3. Model for histone gene activation in mammals

(A) Activation of histone H2B. Oct-1 binds to octamer elements in H2B promoter. During S phase, activated cyclin E/CDK2 complex phosphorylates NPAT. In combination with NPAT, Oct-1 recruits OCA-S to H2B promoter to activates the expression of H2B. The NAD⁺/NADH directly controls the transcription of the H2B gene via regulating the interaction between Oct-1 and OCA-S. (B) Activation of histone H4. HiNF-P binds to SSRE within H4 promoters and recruits NAPT and RNA polymerase II to activate gene transcription. NPAT recruits the Tip60 histone acetyltransferase complex to acetylate histone H4 at the G1/S-phase transition. At the end of S phase, the tyrosine kinase WEE1 is recruited to histone promoters to phosphorylate H2B tyrosine 37, which evicts NPAT and RNA polymerase II and instead recruits HIRA to repress histone gene expression. Figures were adapted from [83]. NPAT, Nuclear Protein Ataxia-Telangiectasia Locus; RNAPII, RNA polymerase II; TRRAP, transformation/transactivation domain-associated protein; SSRE, subtype-specific regulatory elements; OCA-S, Oct-1 co-activator in S-phase; HiNF-P, histone nuclear factor P; TBP, TATA-box binding protein.