Non-canonical Functions of Enhancers: Regulation of RNA Polymerase III Transcription, DNA Replication, and V(D)J Recombination

Overview

Journal Trends Genet

Specialty Genetics

Date 2024 Apr 20

PMID 38643034

Authors

Kevin Struhl

Affiliations

Soon will be listed here.

Abstract

Enhancers are the key regulators of other DNA-based processes by virtue of their unique ability to generate nucleosome-depleted regions in a highly regulated manner. Enhancers regulate cell-type-specific transcription of tRNA genes by RNA polymerase III (Pol III). They are also responsible for the binding of the origin replication complex (ORC) to DNA replication origins, thereby regulating origin utilization, replication timing, and replication-dependent chromosome breaks. Additionally, enhancers regulate V(D)J recombination by increasing access of the recombination-activating gene (RAG) recombinase to target sites and by generating non-coding enhancer RNAs and localized regions of trimethylated histone H3-K4 recognized by the RAG2 PHD domain. Thus, enhancers represent the first step in decoding the genome, and hence they regulate biological processes that, unlike RNA polymerase II (Pol II) transcription, do not have dedicated regulatory proteins.

Citing Articles

Chromatin accessibility: biological functions, molecular mechanisms and therapeutic application.

Chen Y, Liang R, Li Y, Jiang L, Ma D, Luo Q Signal Transduct Target Ther. 2024; 9(1):340.

PMID: 39627201 PMC: 11615378. DOI: 10.1038/s41392-024-02030-9.

References

Bhaumik S, Green M . SAGA is an essential in vivo target of the yeast acidic activator Gal4p. Genes Dev. 2001; 15(15):1935-45. PMC: 312746. DOI: 10.1101/gad.911401. View

de Chasseval R, De Villartay J . Functional characterization of the promoter for the human germ-line T cell receptor J alpha (TEA) transcript. Eur J Immunol. 1993; 23(6):1294-8. DOI: 10.1002/eji.1830230616. View

Li X, Bhaumik S, Zhu X, Li L, Shen W, Dixit B . Selective recruitment of TAFs by yeast upstream activating sequences. Implications for eukaryotic promoter structure. Curr Biol. 2002; 12(14):1240-4. DOI: 10.1016/s0960-9822(02)00932-6. View

Oler A, Alla R, Roberts D, Wong A, Hollenhorst P, Chandler K . Human RNA polymerase III transcriptomes and relationships to Pol II promoter chromatin and enhancer-binding factors. Nat Struct Mol Biol. 2010; 17(5):620-8. PMC: 2945309. DOI: 10.1038/nsmb.1801. View

Ramon-Maiques S, Kuo A, Carney D, Matthews A, Oettinger M, Gozani O . The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2. Proc Natl Acad Sci U S A. 2007; 104(48):18993-8. PMC: 2141896. DOI: 10.1073/pnas.0709170104. View

Miotto B, Struhl K . HBO1 histone acetylase activity is essential for DNA replication licensing and inhibited by Geminin. Mol Cell. 2010; 37(1):57-66. PMC: 2818871. DOI: 10.1016/j.molcel.2009.12.012. View

Barski A, Chepelev I, Liko D, Cuddapah S, Fleming A, Birch J . Pol II and its associated epigenetic marks are present at Pol III-transcribed noncoding RNA genes. Nat Struct Mol Biol. 2010; 17(5):629-34. PMC: 2917008. DOI: 10.1038/nsmb.1806. View

Yague-Sanz C, Migeot V, Larochelle M, Bachand F, Wery M, Morillon A . Chromatin remodeling by Pol II primes efficient Pol III transcription. Nat Commun. 2023; 14(1):3587. PMC: 10276017. DOI: 10.1038/s41467-023-39387-4. View

Gellert M . V(D)J recombination: RAG proteins, repair factors, and regulation. Annu Rev Biochem. 2002; 71:101-32. DOI: 10.1146/annurev.biochem.71.090501.150203. View

10.

CHANDLER V, Maler B, Yamamoto K . DNA sequences bound specifically by glucocorticoid receptor in vitro render a heterologous promoter hormone responsive in vivo. Cell. 1983; 33(2):489-99. DOI: 10.1016/0092-8674(83)90430-0. View

11.

Canella D, Bernasconi D, Gilardi F, LeMartelot G, Migliavacca E, Praz V . A multiplicity of factors contributes to selective RNA polymerase III occupancy of a subset of RNA polymerase III genes in mouse liver. Genome Res. 2012; 22(4):666-80. PMC: 3317149. DOI: 10.1101/gr.130286.111. View

12.

Brown D, Schlissel M . A positive transcription factor controls the differential expression of two 5S RNA genes. Cell. 1985; 42(3):759-67. DOI: 10.1016/0092-8674(85)90272-7. View

13.

Iyer V, Struhl K . Mechanism of differential utilization of the his3 TR and TC TATA elements. Mol Cell Biol. 1995; 15(12):7059-66. PMC: 230961. DOI: 10.1128/MCB.15.12.7059. View

14.

Schatz D, Oettinger M, Baltimore D . The V(D)J recombination activating gene, RAG-1. Cell. 1989; 59(6):1035-48. DOI: 10.1016/0092-8674(89)90760-5. View

15.

Mertens C, Roeder R . Different functional modes of p300 in activation of RNA polymerase III transcription from chromatin templates. Mol Cell Biol. 2008; 28(18):5764-76. PMC: 2546916. DOI: 10.1128/MCB.01262-07. View

16.

Nolis I, McKay D, Mantouvalou E, Lomvardas S, Merika M, Thanos D . Transcription factors mediate long-range enhancer-promoter interactions. Proc Natl Acad Sci U S A. 2009; 106(48):20222-7. PMC: 2779200. DOI: 10.1073/pnas.0902454106. View

17.

Lorch Y, Maier-Davis B, Kornberg R . Role of DNA sequence in chromatin remodeling and the formation of nucleosome-free regions. Genes Dev. 2014; 28(22):2492-7. PMC: 4233242. DOI: 10.1101/gad.250704.114. View

18.

Koch C, Andrews R, Flicek P, Dillon S, Karaoz U, Clelland G . The landscape of histone modifications across 1% of the human genome in five human cell lines. Genome Res. 2007; 17(6):691-707. PMC: 1891331. DOI: 10.1101/gr.5704207. View

19.

Wade J, Reppas N, Church G, Struhl K . Genomic analysis of LexA binding reveals the permissive nature of the Escherichia coli genome and identifies unconventional target sites. Genes Dev. 2005; 19(21):2619-30. PMC: 1276735. DOI: 10.1101/gad.1355605. View

20.

May M, Bettridge J, Desiderio S . Binding and allosteric transmission of histone H3 Lys-4 trimethylation to the recombinase RAG-1 are separable functions of the RAG-2 plant homeodomain finger. J Biol Chem. 2020; 295(27):9052-9060. PMC: 7335790. DOI: 10.1074/jbc.RA120.014382. View