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Mapping the retrotransposon-mediated layer of neuronal gene regulation in the human genome

Periodic Reporting for period 2 - PRIMATE-TE-IMPACT (Mapping the retrotransposon-mediated layer of neuronal gene regulation in the human genome)

Reporting period: 2019-02-01 to 2020-07-31

The Primate-TE-Impact research program investigates the influence of transposable elements (TEs), parasitic DNA sequences in our genome and their KRAB zinc finger repressor proteins (KZNFs), on the expression of neuronal genes. My lab investigates to which extent recent retrotransposon invasions have shaped gene-regulatory networks that drive human neuronal development and explores how some of these changes may have made our brain more susceptible to disease. Based on preliminary findings, this research program explores to which extent loss of silencing of retrotransposons, as a result of an altered epigenetic landscape, is responsible for dysregulation of genes associated with neurological diseases. Our discoveries may form the basis of a novel concept which can explain how changes in the epigenetic landscape can uncover a dormant genetic predisposition to disease.
We made the first important steps to determine how recent retrotransposon insertions have shaped gene-regulatory pathways involved in human brain development. Using CRISPR/Cas9-mediated genetic deletion techniques to knock out KRAB zinc fingers from the human genome, we are starting to observe that some classes of primate-specific TEs have had a measurable influence on gene expression in embryonic stem cell-derived cortical organoids. These KRAB zinc fingers and the TEs that they have evolved to repress are currently investigated in more detail.

As one unexpected outcome of these experiments, we found that in addition to their role in repressing TEs, KRAB zinc finger genes are also important for regulation of genes independent from TE insertions. A paper describing this phenomenon was recently published (Farmiloe et al., 2020).

We have become particularly interested in primate-specific TE insertions in genetic loci associated with human neurological diseases and have engaged in a number of collaborations to study their potential impact on the susceptibility of these diseases. We have recently started to apply CRISPR/Cas9 to genetically delete or regulate specific TEs from our genome to assess their impact on gene regulating by analyzing the resulting changes on both epigenetic and transcriptomic level. Most of the analysis is done in cortical organoids to obtain a clear view of how the TE insertion has affected neuronal gene expression when it inserted in the locus at some point during primate evolution.
Next to the work we published in the last years, at the moment, we have two manuscripts submitted for publication and three finalized studies being prepared for submission. These works represent the foundation of what we aimed to investigate in this research program. Importantly, some unexpected observations we made in the first half of the ERC project has provided valuable new insights leading to new hypotheses and a novel unexplored angle regarding the evolutionary impact of TEs and their KRAB Zinc finger repressors. These hypotheses are subject to my lab’s investigations in the next phase of the ERC starting grant.