Bluma Lesch, MD, PhD
Research & Publications
Biography
News
Research Summary
Germ cells (sperm, eggs, and their developmental precursors) carry the genome from one generation to the next. The germ cell nucleus therefore carries all the information that will guide the development of the next generation, and that will subsequently be passed to future generations to ensure the survival of the species. How the physical genome is handled within the germ cells thus has significant implications for development of individuals and for evolution of species. Our lab aims to define how packaging of the genome in germ cells influences these processes. We compare chromatin states in germ cells across species to understand how genome regulation has evolved, and we use mouse genetics to model the molecular basis of these processes and their direct effects on embryo development.
We have previously shown that epigenetic poising, a chromatin state characterized by the simultaneous presence of both activating and repressive histone marks and strongly associated with pluripotent stem cells, is a fundamental characteristic of mammalian germ cells beginning at early stages of development and specifically marks genes required for embryogenesis in the next generation. Furthermore, poising is conserved in the amniote germ line, but evolves at specific locations in individual lineages in conjunction with developmental innovations. These findings imply that poising in the germ line may help to protect or ‘set aside’ regions of the genome that are particularly important for early embryonic development. We are currently pursuing this hypothesis, as well as examining additional aspects of germ cell genome regulation. See the lab website for more information about current projects.
Coauthors
Research Interests
Embryonic and Fetal Development; Gene Expression Regulation; Germ Cells; Reproduction; Stem Cells; Evolution, Molecular; Computational Biology; Heredity; Chromatin Assembly and Disassembly; Epigenetic Memory
Selected Publications
- DOT1L bridges transcription and heterochromatin formation at mammalian pericentromeresMalla A, Yu H, Farris D, Kadimi S, Lam T, Cox A, Smith Z, Lesch B. DOT1L bridges transcription and heterochromatin formation at mammalian pericentromeres. EMBO Reports 2023, 24: e56492. PMID: 37317657, PMCID: PMC10398668, DOI: 10.15252/embr.202256492.
- DOT1L promotes spermatid differentiation by regulating expression of genes required for histone-to-protamine replacementMalla A, Rainsford S, Smith Z, Lesch B. DOT1L promotes spermatid differentiation by regulating expression of genes required for histone-to-protamine replacement. Development 2023, 150 PMID: 37082969, PMCID: PMC10259660, DOI: 10.1242/dev.201497.
- Deconvolution of in vivo protein-RNA contacts using fractionated eCLIP-seqBiancon G, Busarello E, Joshi P, Lesch B, Halene S, Tebaldi T. Deconvolution of in vivo protein-RNA contacts using fractionated eCLIP-seq. STAR Protocols 2022, 3: 101823. PMCID: PMC9676202, DOI: 10.1016/j.xpro.2022.101823.
- Deconvolution of in vivo protein-RNA contacts using fractionated eCLIP-seqBiancon G, Busarello E, Joshi P, Lesch B, Halene S, Tebaldi T. Deconvolution of in vivo protein-RNA contacts using fractionated eCLIP-seq. STAR Protocols 2022, 3: 101823. PMID: 36595959, PMCID: PMC9676202, DOI: 10.1016/j.xpro.2022.101823.
- Widespread association of the Argonaute protein AGO2 with meiotic chromatin suggests a distinct nuclear function in mammalian male reproductionGriffin KN, Walters BW, Li H, Wang H, Biancon G, Tebaldi T, Kaya CB, Kanyo J, Lam TT, Cox AL, Halene S, Chung JJ, Lesch BJ. Widespread association of the Argonaute protein AGO2 with meiotic chromatin suggests a distinct nuclear function in mammalian male reproduction. Genome Research 2022, 32: 1655-1668. PMID: 36109149, PMCID: PMC9528986, DOI: 10.1101/gr.276578.122.
- Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansionsChandrasekaran S, Espeso-Gil S, Loh YE, Javidfar B, Kassim B, Zhu Y, Zhang Y, Dong Y, Bicks LK, Li H, Rajarajan P, Peter CJ, Sun D, Agullo-Pascual E, Iskhakova M, Estill M, Lesch BJ, Shen L, Jiang Y, Akbarian S. Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions. Nature Communications 2021, 12: 7243. PMID: 34903713, PMCID: PMC8669064, DOI: 10.1038/s41467-021-26862-z.
- Epigenetic states in the human placenta: A singular epigenome for an exceptional tissueLesch BJ. Epigenetic states in the human placenta: A singular epigenome for an exceptional tissue. Developmental Cell 2021, 56: 1211-1212. PMID: 33945779, DOI: 10.1016/j.devcel.2021.04.011.
- H3K4me1 Distribution Predicts Transcription State and Poising at PromotersBae S, Lesch BJ. H3K4me1 Distribution Predicts Transcription State and Poising at Promoters. Frontiers In Cell And Developmental Biology 2020, 8: 289. PMID: 32432110, PMCID: PMC7214686, DOI: 10.3389/fcell.2020.00289.
- Sperm Go to (Transcription) ExtremesLesch BJ. Sperm Go to (Transcription) Extremes. Cell 2020, 180: 212-213. PMID: 31978338, DOI: 10.1016/j.cell.2019.12.033.
- A universal transportin protein drives stochastic choice of olfactory neurons via specific nuclear import of a sox-2-activating factorAlqadah A, Hsieh YW, Xiong R, Lesch BJ, Chang C, Chuang CF. A universal transportin protein drives stochastic choice of olfactory neurons via specific nuclear import of a sox-2-activating factor. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 25137-25146. PMID: 31767767, PMCID: PMC6911211, DOI: 10.1073/pnas.1908168116.
- Intergenerational epigenetic inheritance of cancer susceptibility in mammalsLesch BJ, Tothova Z, Morgan EA, Liao Z, Bronson RT, Ebert BL, Page DC. Intergenerational epigenetic inheritance of cancer susceptibility in mammals. ELife 2019, 8: e39380. PMID: 30963999, PMCID: PMC6456297, DOI: 10.7554/elife.39380.
- Erratum: Corrigendum: Parallel evolution of male germline epigenetic poising and somatic development in animalsLesch B, Silber S, McCarrey J, Page D. Erratum: Corrigendum: Parallel evolution of male germline epigenetic poising and somatic development in animals. Nature Genetics 2016, 48: 1296-1296. PMID: 27681290, DOI: 10.1038/ng1016-1296b.
- Parallel evolution of male germline epigenetic poising and somatic development in animalsLesch BJ, Silber SJ, McCarrey JR, Page DC. Parallel evolution of male germline epigenetic poising and somatic development in animals. Nature Genetics 2016, 48: 888-894. PMID: 27294618, DOI: 10.1038/ng.3591.
- Poised chromatin in the mammalian germ lineLesch BJ, Page DC. Poised chromatin in the mammalian germ line. Development 2014, 141: 3619-3626. PMID: 25249456, PMCID: PMC4197577, DOI: 10.1242/dev.113027.
- A Chromatin-Dependent Role of the Fragile X Mental Retardation Protein FMRP in the DNA Damage ResponseAlpatov R, Lesch BJ, Nakamoto-Kinoshita M, Blanco A, Chen S, Stützer A, Armache KJ, Simon MD, Xu C, Ali M, Murn J, Prisic S, Kutateladze TG, Vakoc CR, Min J, Kingston RE, Fischle W, Warren ST, Page DC, Shi Y. A Chromatin-Dependent Role of the Fragile X Mental Retardation Protein FMRP in the DNA Damage Response. Cell 2014, 157: 869-881. PMID: 24813610, PMCID: PMC4038154, DOI: 10.1016/j.cell.2014.03.040.
- A set of genes critical to development is epigenetically poised in mouse germ cells from fetal stages through completion of meiosisLesch BJ, Dokshin GA, Young RA, McCarrey JR, Page DC. A set of genes critical to development is epigenetically poised in mouse germ cells from fetal stages through completion of meiosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 16061-16066. PMID: 24043772, PMCID: PMC3791702, DOI: 10.1073/pnas.1315204110.
- The Ligand Binding Domain of GCNF Is Not Required for Repression of Pluripotency Genes in Mouse Fetal Ovarian Germ CellsOkumura LM, Lesch BJ, Page DC. The Ligand Binding Domain of GCNF Is Not Required for Repression of Pluripotency Genes in Mouse Fetal Ovarian Germ Cells. PLOS ONE 2013, 8: e66062. PMID: 23762465, PMCID: PMC3676325, DOI: 10.1371/journal.pone.0066062.
- Sex-specific chromatin states in mammalian fetal germ cellsLesch B, Page D. Sex-specific chromatin states in mammalian fetal germ cells. Epigenetics & Chromatin 2013, 6: p45. PMCID: PMC3600753, DOI: 10.1186/1756-8935-6-s1-p45.
- Genetics of germ cell developmentLesch BJ, Page DC. Genetics of germ cell development. Nature Reviews Genetics 2012, 13: 781-794. PMID: 23044825, DOI: 10.1038/nrg3294.