Research in my laboratory investigates new mechanisms of gene regulation by short RNAs and chromatin-modifying complexes.
A major focus of our work is the metazoan DOT1L methyltransferase complex. DOT1L is essential for development, it is an emerging oncoprotein implicated in numerous cancers, and it has recently been connected to control of mitochondrial genes and adipose tissue health.
My lab studies gene regulation by the DOT1L complex in C. elegans, mammalian cells and zebrafish, including enhancer regulation, control of non-coding transcriptome, and cooperation with MYC.
When investigating coordinate gene regulation by DOT1L and MYC we found a new biochemical function of DOT1L that we are actively studying now.
Recently, we uncovered a long-sought link between DOT1L and RNAi by finding overactivation of endogenous RNAi in dot-1 mutant worms. This likely leads to epigenetic inheritance of ectopic small RNAs and/or aberrant chromatin states and accounts for many developmental problems of the mutants. We are testing this possibility. Also, it would be interesting to know whether there are ectopic small RNAs in mammalian cells lacking DOT1L.
Overall, we are interested in connecting our findings to the genetics and epigenetics of human disease.
Laboratory Members
Valentina Pannarale – Undergraduate Student
Sasiru Pathiranage – Undergraduate Student
Representative Publications
- Liontis T, Verma K, Grishok A. DOT-1.1 (DOT1L) deficiency in C. elegans leads to small RNA-dependent gene activation. BBA Adv. 2023; 3:100080. PMID: 37082252; PMCID: PMC10074844; DOI: 10.1016/j.bbadva.2023.100080;
- Grishok A. Small RNAs Worm Up Transgenerational Epigenetics Research. DNA (Basel). 2021 Dec; 1(2):37-48. PMID: 34725653; PMCID: PMC8556531; DOI: 10.3390/dna1020005;
- Lascarez-Lagunas LI, Herruzo E, Grishok A, San-Segundo PA, Colaiácovo MP. DOT-1.1-dependent H3K79 methylation promotes normal meiotic progression and meiotic checkpoint function in C. elegans. PLoS Genet. 2020 10; 16(10):e1009171. PMID: 33104701
- Esse R, Grishok A. Caenorhabditis elegans Deficient in DOT-1.1 Exhibit Increases in H3K9me2 at Enhancer and Certain RNAi-Regulated Regions. Cells. 2020 Aug 6;9(8):E1846. doi: 10.3390/cells9081846.
- Esse R, Gushchanskaia ES, Lord A, Grishok A. DOT1L complex suppresses transcription from enhancer elements and ectopic RNAi in Caenorhabditis elegans. RNA. 2019 10; 25(10):1259-1273. PMID:31300558
- Zaarur N, Desevin K, Mackenzie J, Lord A, Grishok A, Kandror KV. ATGL-1 mediates the effect of dietary restriction and the insulin/IGF-1 signaling pathway on longevity in C. elegans. Mol Metab. 2019 09; 27:75-82. PMID: 31311719
- Gushchanskaia ES, Esse R, Ma Q, Lau NC, Grishok A. Interplay between small RNA pathways shapes chromatin landscapes in C. elegans. Nucleic Acids Res. 2019 06 20; 47(11):5603-5616.PMID: 31216042
- Cecere G, Grishok A. RNA Chromatin Immunoprecipitation (RNA-ChIP) in Caenorhabditis elegans. Bio Protoc. 2014 Dec 20; 4(24). PMID: 29170745
- Cecere G, Hoersch S, O’Keeffe S, Sachidanandam R, Grishok A. Global effects of the CSR-1 RNA interference pathway on the transcriptional landscape. Nat Struct Mol Biol. 2014 Apr; 21(4):358-65. PMID: 24681887
- Kennedy LM, Grishok A. Neuronal migration is regulated by endogenous RNAi and chromatin-binding factor ZFP-1/AF10 in Caenorhabditis elegans. Genetics. 2014 May; 197(1):207-20. PMID:24558261
- Cecere G, Grishok A. A nuclear perspective on RNAi pathways in metazoans. Biochim Biophys Acta. 2014 Mar; 1839(3):223-33. PMID: 24361586
- Kennedy LM, Pham SC, Grishok A. Nonautonomous regulation of neuronal migration by insulin signaling, DAF-16/FOXO, and PAK-1. Cell Rep. 2013 Sep 12; 4(5):996-1009. PMID: 23994474
- Cecere G, Hoersch S, Jensen MB, Dixit S, Grishok A. The ZFP-1(AF10)/DOT-1 complex opposes H2B ubiquitination to reduce Pol II transcription. Mol Cell. 2013 Jun 27; 50(6):894-907. PMID: 23806335
- Grishok A. Biology and Mechanisms of Short RNAs in Caenorhabditis elegans. Adv Genet. 2013; 83:1-69. PMID: 23890211
Complete list can be found at BU Profiles
