Title: AMS Professorship award for Professor Juanma Vaquerizas, Imperial College London
Funder: The Academy of Medical Sciences

Abstract: In the work I propose here, I aim to capitalise on our previously gained expertise in examining chromatin conformation during early development and regulation mediated by repetitive elements to address two key questions of my research programme: i) the maternal-paternal allele-specific regulation of repetitive elements in early mammalian embryogenesis; and, ii) the identification of human-specific regulatory networks in spermatogenesis. For the first question, an ample body of work has identified and highlighted the marked maternal and paternal differences related to the production of gametes and the reversal of the maternal and paternal pro-nuclei from a fully differentiated gamete state to a totipotent state. These include hallmark molecular mechanisms such as the paternal swap of histones for protamines during sperm maturation, genomic imprinting, and the active demethylation of the paternal genome following fertilisation (Vaquerizas and Hug, Trend Genet. 2018). The latter is of particular interest, since DNA methylation is meant to account for the specific silencing of repetitive elements, which is fundamental to maintain genome integrity and stability. Here, using publicly available genomic datasets for mouse early embryonic development, we will establish the extent of allele-specific regulation at repetitive element regions during this developmental stage. This will determine whether the distinct changes in chromatin conformation that we previously identified originate from the maternal or paternal allele and therefore, the role that active paternal DNA methylation plays in this process. For the second question, recent groundbreaking work examining 3D chromatin organisation has revealed major species-specific differences during sperm maturation in primates and mammals (Chen et al., Nature 2019). However, the regulatory mechanisms that determine these differences are not known. Here, we will unveil the regulatory network responsible for the human-specific degradation of CTCF, a key component of the 3D genome machinery, in mature sperm. To do so, in collaboration with the Centre for Reproduction (University Hospital Muenster), we will produce single-cell ATAC-seq datasets to identify the set of open chromatin regulatory regions during normal spermatogenesis. Integrative computational analysis of these datasets and publicly available single-cell RNA-seq datasets for the same differentiation process will reveal the regulatory networks driving human spermatogenesis. Finally, comparative evolutionary analysis with equivalent publicly available datasets for mice will unveil the human-specific components of this regulatory network, which we will then validate in tissue culture using CRISPR-based endogenous overexpression strategies (CRISPRa). Having spent my postdoctoral training at the European Bioinformatics Institute and University of Cambridge, I have a solid UK-based research network mostly focused on basic molecular biology and genomics. However, my recent work at the Max Planck Institute for Molecular Biomedicine has developed a substantial disease-oriented focus. The AMS Professorship will ensure that I can build an updated network to cater for these needs though interactions with the Fellowship and participation in AMS events. Crucially, the flexibility in the funding provided through the Professorship will also ensure that my laboratory has a smooth transition from Germany to the UK, which will allow us to maintain our high scientific productivity in an extremely competitive field.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH