DNA is methylated on cytosine in the context of CpG dinucleotide in mammalian cells. The absence of such methylation in CpG-rich promoter regions known as CpG islands (CGIs) is a hallmark of transcriptional activity. In contrast, CpGs in intergenic and intronic regions are frequently heavily methylated. Such methylation likely serves to maintain transposable elements in these regions in a transcriptionally inert state. Although the mammalian “de novo” DNA methyltransferases Dnmt3A and Dnmt3B were cloned several years ago, very little is known about the mechanism by which specific regions of the genome are targeted for methylation by these enzymes. As CpG islands are typically a kilobase or longer in length, it is likely that some attribute of chromatin structure, rather than transcription factor binding per se, protects these regions from de novo methylation. Whatever the nature of this protective affect, it clearly breaks down in cancer cells, in which CGIs are frequently aberrantly methylated, coincident with hypomethylation of the rest of the genome.
Recently, a number of factors have been described that catalyze the post-translational addition or removal of specific moieties, such as acetyl or methyl groups, to/from specific residues on the core nucleosomal histones. A subset of these ‘histone-modifying enzymes’, including histone acetyltransferases and histone H3 lysine 4 (H3K4) methyltransferases, are required for transcription. Intriguingly, histones associated with the promoter regions of actively transcribing genes are marked by a unique combination of covalent modifications, including H3K4 methylation, which may serve to protect promoters from DNA methylation. Conversely, the presence of repressive histone marks, such as H3K9me3 and H3K36me3, in promoter regions and gene bodies, respectively, may promote methylation of associated DNA.
Research in the lab is directed towards understanding the interplay between transcription, DNA methylation and histone modifications in early development and in the germline, using the mouse as a model system. We employ CRISPR/Cas9 and conventional genetic knockouts of chromatin factors or regulatory regions with genome-wide analyses of chromatin structure and function to dissect the roles of specific epigenetic marks in the regulation of genes, retroelements and chimaeric transcripts. These studies are made possible by low-cell input methods for whole genome analysis of chromatin marks (ULI-ChIP-seq), DNA methylation (PBAT) and transcription (RNAseq), and in house pipelines developed to integrate the analyses of these epigenomic datasets at an allele-specific level.
Ongoing projects include: 1) dissecting the interplay between the histone modifications H3K36me2 and H3K27me3, deposited by NSD1 and EZH2, respectively, in early embryonic development to define the molecular basis of the related overgrowth disorders Sotos and Weaver Syndromes; 2) characterizing the “heritability” of covalent histone modifications and DNA methylation through fertilization using F1 hybrid mice and allele-specific analyses; 3) characterizing the role of H3K9 “writers” (methyltransferases) and “readers” in transcriptional regulation and 4) characterizing the role of LTR-initiated transcripts in the establishment of imprinting in oocytes.
For Professor Lorincz’s up-to-date publication list, please see the following link:
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Hu, C.-K. et al. Vertebrate diapause preserves organisms long term through Polycomb complex members. Science 367, 870–874 (2020).
Bogutz AB, Brind’Amour J, Kobayashi H, Jensen KN, Nakabayashi K, Imai H, Lorincz MC, Lefebvre L
Evolution of Imprinting via lineage-specific insertion of retroviral promoters
Nat Commun. 2019 December;10(1):5674, doi:10.1038/s41467-019-13662-9
Xu Q, Xiang Y, Wang Q, Wang L, Brind’Amour J, Bogutz AB, Zhang Y, Zhang B, Yu G, Xia W, Du Z, Huang C, Ma J, Zheng H, Li Y, Liu C, Walker CL, Jonasch E, Lefebvre L, Wu M, Lorincz MC, Li W, Li L, Xie W.
SETD2 regulates the maternal epigenome, genomic imprinting and embryonic development.
Nature Genetics. 2019 May;51(5), 844-856. doi: 10.1038/s41588-019-0398-7
Au Yeung WK, Brind’Amour J, Hatano Y, Yamagata K, Feil R, Lorincz MC, Tachibana M, Shinkai Y, Sasaki H.
Histone H3K9 Methyltransferase G9a in Oocytes Is Essential for Preimplantation Development but Dispensable for CG Methylation Protection.
Cell Reports. 2019 April;27(1), 282-293.e4. doi:10.1016/j.celrep.2019.03.002
Brind’Amour J, Kobayashi H, Richard Albert J, Shirane K, Sakashita A, Kamio A, Bogutz A, Koike T, Karimi MM, Lefebvre L, Kono T, Lorincz MC.
LTR retrotransposons transcribed in oocytes drive species-specific and heritable changes in DNA methylation.
Nat Commun. 2018 August;9(1):3331. doi: 10.1038/s41467-018-05841-x
Richard Albert J, Koike T, Younesy H, Thompson R, Bogutz AB, Karimi MM, Lorincz MC.
Development and application of an integrated allele-specific pipeline for methylomic and epigenomic analysis (MEA)
BMC Genomics. 2018 June;19(1), 125. doi: 10.1186/s12864-018-4835-2
Jensen KN, Lorincz MC.
HP1 proteins safeguard embryonic stem cells
Nature. 2018 May;557(7707):640-641. doi: 10.1038/d41586-018-05188-9.
Chen CCL, Goyal P, Karimi MM, Abildgaard MH, Kimura H, Lorincz MC.
H3S10ph broadly marks early-replicating domains in interphase ESCs and shows reciprocal antagonism with H3K9me2.
Genome Res. 2018 Jan;28(1):37-51. doi: 10.1101/gr.224717.117. Epub 2017 Dec 11.
Lorincz MC, Schübeler D.
Evidence for converging DNA methylation pathways in placenta and cancer.
Dev Cell. (2017) 43(3):257-258. doi: 10.1016/j.devcel.2017.10.009.
Wolf G, Rebollo R, Karimi MM, Ewing AD, Kamada R, Wu W, Wu B, Bachu M, Ozato K, Faulkner GJ, Mager DL, Lorincz MC, Macfarlan.
On the role of H3.3 in retroviral silencing.
Nature. (2017) 548(7665):E1-E3.
Mager DL & Lorincz MC.
Epigenetic modifier drugs trigger widespread transcription of endogenous retroviruses.
Nature Genetics. (2017) 49, 974-975. doi:10.1038/ng.3902