Chromatin and Development

“We study how transposons have been co-opted to regulate essential processes in development, and how their misregulation may contribute to disease.”

In early development, a single fertilized zygote proceeds through a series of cleavage steps to develop into a multicellular blastocyst. The cells of the blastocyst are capable of generating all adult cell types, a phenomenon known as pluripotency. The inner cell mass (ICM) of the blastocyst can moreover be cultured in vitro as pluripotent embryonic stem (ES) cells, which have become invaluable tools for understanding development and for regenerative medicine.

The broad focus of our lab is the transcriptional and epigenetic regulation of early development. In particular, we are interested in understanding the importance of transposable elements (TEs) in development and disease. TE sequences make up nearly 50% of our genomes, yet have been greatly understudied. TE reactivation has been recently linked to several diseases such as cancer and neuroinflammation. Intriguingly however, our work as well as several others’ has highlighted the dynamic expression of several TE families during normal development, as well as their functional importance in embryogenesis.

Percharde image

Dynamic expression in of TEs in development. Fluorescence images depicting MERVL gag protein expressed specifically in 2C-like cells (left), and abundant nuclear LINE1 RNA expression in ES cells (right).

Using mouse and human ES cells and mouse embryo models, we are investigating how TE networks function in distinct stages of mammalian development. We employ a combination of candidate and genome-wide approaches, CRISPR technology, imaging and bioinformatics to describe and dissect TE function in embryogenesis and cell fate choices. We additionally explore how pathways that regulate TE expression may fail in cases of disease.

Chromatin and Development

The LTR transposon, ERVL (MERVL, MuERV-L) is highly and transiently activated in totipotent 2-cell mouse embryos, along with several hundred ERVL-driven 2-cell specific transcripts. We aim to understand more about the protein complexes and signaling pathways that regulate MERVL exit and entry from totipotency in vitro and in vivo.

Michelle Percharde holds a UKRI Future Leaders Fellowship

Selected Publications

Mau, K.H.T., Karimlou, D., Barneda, D., Brochard V., Royer C., Leeke B., A de Souza R., Pailles M., Percharde M., Srinivas S., Jouneau A., Christian M., Azuara V. (2022) Dynamic enlargement and mobilization of lipid droplets in pluripotent cells coordinate morphogenesis during mouse peri-implantation development. Nat Commun 13, 3861.

Xie SQLeeke BJ, Whilding C, Wagner RT, Garcia-Llagostera F, Low XY, Chammas P, Cheung NT-F, Dormann D, McManus MT, Percharde M. (2022) Nucleolar-based Dux repression is essential for embryonic two-cell stage exitGenes Dev, Mar 10. doi: 10.1101/gad.349172.121 

Percharde M, Sultana T & Ramalho-Santos M. (2020). What Doesn’t Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation. Bioessays; 42, 4.

Lu JY, Shao W, Chang L, Yin Y, Li T, Zhang H, Hong Y, Percharde M, Guo L, Wu Z, Liu L, Liu W, Yan P, Ramalho-Santos M, Sun Y, Shen X. (2020). Genomic Repeats Categorize Genes With Distinct Functions for Orchestrated Regulation. Cell Reports,10;30(10):3296-3311.e5

DiTroia SP, Percharde M, Guerquin M, Wall E, Collignon E, Ebata KT, Mesh K, Mahesula S, Agathocleous M, Laird DJ, Livera G, Ramalho-Santos M. (2019). Maternal vitamin C regulates reprogramming of DNA methylation and germline development. Nature. 573, 271-275.

Percharde M, Lin C-J, Yin Y, Guan J, Peixoto GA, Bulut-Karslioglu A, Biechele S, Huang B, Shen X, Ramalho-Santos M. (2018). A LINE1-Nucleolin Partnership Regulates Early Development and ESC Identity. Cell. 174, 391-405.

Bulut-Karslioglu A, Macrae TA, Oses-Prieto JA, Covarrubias S, Percharde M, Ku G, Diaz A, McManus MT, Burlingame AL, Ramalho-Santos M. (2018). The Transcriptionally Permissive Chromatin State of Embryonic Stem Cells Is Acutely Tuned to Translational Output. Cell Stem Cell. 22, 369-383

Percharde M, Wong P, Ramalho-Santos M. (2017). Global Hypertranscription in the Mouse Embryonic Germline. Cell Reports19, 1987-1996.

Percharde M, Bulut-Karslioglu A, Ramalho-Santos M. (2017). Hypertranscription in Development, Stem Cells, and Regeneration. Developmental Cell. 40, 9-21.

Qin H, Hejna M, Liu Y, Percharde M, Wossidlo M, Blouin L, Durruthy-Durruthy J, Wong P, Qi Z, Yu J, Qi LS, Sebastiano V, Song JS, Ramalho-Santos M. (2016). YAP Induces Human Naive Pluripotency. Cell Reports. 14, 2301-2312.

Percharde M, Lavial F, Ng J-H, Kumar V, Tomaz RA, Martin N, Yeo J-C, Gil J, Prabhakar S, Ng H-H, Parker MG, Azuara V. (2012). Ncoa3 functions as an essential Esrrb coactivator to sustain embryonic stem cell self-renewal and reprogrammingGenes & Development. 26, 2286-2298.