Genome regulation depends on coordinated changes in 3D genome organization and the transcriptome, whose interaction directs cell fate decisions. This coordination is particularly crucial post fertilization, when de novo establishment of genome organization and gene expression patterns guides the first lineage specification into embryonic and extraembryonic tissues. How transcriptional programs and 3D genome structure are established and how their interplay generates distinct cell lineages remain fundamental questions in biology. Our goal is to uncover the molecular components and mechanisms by which dark genome elements – genomic regions with a poorly understood role – modulate genome function and act as a novel regulatory layer driving mammalian development.
Dark genome elements constitute over 50% of the mammalian genome. They include transposons, repeats, lncRNAs, and other non-canonical genes. Once dismissed as genomic noise or junk DNA, these elements are now recognized as powerful regulators of gene expression and nuclear organization. Recent work from our lab and others shows that DNA, RNA and proteins derived from these elements regulate early developmental transitions. Yet, the precise mechanisms and molecules that are functional are not well understood.
At the Jachowicz lab, we aim to understand how the transcriptional program and 3D genome architecture emerge after fertilization, and how their interplay determines the fate of individual cells in a developing embryo. We specifically focus on the regulatory roles of dark genome elements.
We ask which dark genome products drive cell-state transitions and how they modulate genome architecture and gene expression patterns. We aim to determine whether these elements actively influence or respond to the developmental transitions that drive early embryogenesis.
We believe that by uncovering the precise mechanisms by which dark genome elements influence early development, we build a comprehensive and mechanistic understanding of genome function at the molecular and cellular levels.
Our long-term goal is to clarify the regulatory logic by which dark genome elements influence cell fate and cell-state transitions, and to integrate their functions into a broader framework of genome regulation. By systematically investigating their molecular roles, we strive to reposition the dark genome as an active, functional component of gene regulation during embryogenesis, rather than a passive or incidental genome feature. Ultimately, our work will provide fundamental insights into the molecular forces shaping cell fate decisions and the most profound genome remodeling events in early mammalian life.
ERC Starting Grant (2022-2027)
Arrastia, MV., Jachowicz, JW., Ollikainen, N (...) Ismagilov, RF., Guttman, M. (2022). Single-cell measurement of higher-order 3D genome organization with scSPRITE. Nat Biotechnol. 40(1):64-73
Jachowicz, JW., Strehle, M., Banerjee, AK (...) Thai, J., Guttman, M. (2022). Xist spatially amplifies SHARP/SPEN recruitment to balance chromosome-wide silencing and specificity to the X chromosome. Nat Struct Mol Biol. 29(3):239-249
Quinodoz, SA., Jachowicz, JW., Bhat, P (...) Plath, K., Guttman, M. (2021). RNA promotes the formation of spatial compartments in the nucleus. Cell. 184(23):5775-5790.e30
Jachowicz, JW., Bing, X., Pontabry, J (...) Rando, OJ., Torres-Padilla, ME. (2017). LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo. Nat Genet. 49(10):1502-1510
Jachowicz, JW., Santenard, A., Bender, A., Muller, J., Torres-Padilla, ME. (2013). Heterochromatin establishment at pericentromeres depends on nuclear position. Genes Dev. 27(22):2427-32
