Periodic Reporting for period 4 - PRIMATE-TE-IMPACT (Mapping the retrotransposon-mediated layer of neuronal gene regulation in the human genome)
Reporting period: 2022-02-01 to 2023-01-31
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 found that TEs and KZNFs have a widespread influence on gene regulation, either directly through KZNFs binding to TEs or indirectly through KZNFs binding to gene promoters. These novel gene regulatory properties are highly species specific and form a significant contribution to the differences in gene expression patterns that exist between species. We found that some of these newly acquired gene regulatory properties can have a negative influence on gene control, which seems to become most apparent during aging of cells when the repression of TES may be less effective. The careful dissection of the involvement of TEs and their partner KZNFs in several diseases can provide novel insights into the etiology of diseases and may lead to novel therapeutic strategies and approaches in the future.
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. Two papers describing this phenomenon were published (Farmiloe et al., 2020; Haring et al., 2021).
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 applied 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 was 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. In our publication (Van Bree et al., 2022) in Genome Research, we revealed that numerous SVA insertions, which are fixed in the human population, can exist in structurally different forms in the population. These different polymorphisms can have different effects on genes nearby, genes that are sometimes associated with increased risk for human diseases through GWAS. Because often the causal factor in these disease associeated loci remains unknown, our study puts forward polymorphisms in TEs such as SVAs as potential causal factors that can have a differential effect on genes nearby in different individuals, hence providing a way in which a disease associated gene in one individual may be under a different influence of the SVA insertion than another individual. This provides an explanation for the observed but poorly understood variability of susceptibility to many human neurodegenerative diseases. This study is the first to show that this is the case and has contributed in bringen the attention to the repetitive part of our DNA in search for causal susceptibility factors.
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. Two papers describing this phenomenon were published (Farmiloe et al., 2020; Haring et al., 2021).
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 applied 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 was 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. In our publication (Van Bree et al., 2022) in Genome Research, we revealed that numerous SVA insertions, which are fixed in the human population, can exist in structurally different forms in the population. These different polymorphisms can have different effects on genes nearby, genes that are sometimes associated with increased risk for human diseases through GWAS. Because often the causal factor in these disease associeated loci remains unknown, our study puts forward polymorphisms in TEs such as SVAs as potential causal factors that can have a differential effect on genes nearby in different individuals, hence providing a way in which a disease associated gene in one individual may be under a different influence of the SVA insertion than another individual. This provides an explanation for the observed but poorly understood variability of susceptibility to many human neurodegenerative diseases. This study is the first to show that this is the case and has contributed in bringen the attention to the repetitive part of our DNA in search for causal susceptibility factors.
Our discoveries have unveiled the genome wide influence of TEs and KZNFs on gene expression patterns in human tissues, and our findings reveal the existence of a highly species specific layer of gene control, constituted by both TEs and KRAB Zinc finger genes. In addition, our findings 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 found that TEs and KZNFs have a widespread influence on gene regulation, either directly through KZNFs binding to TEs or indirectly through KZNFs binding to gene promoters. These novel gene regulatory properties are highly species specific and form a significant contribution to the differences in gene expression patterns that exist between species. We found that some of these newly acquired gene regulatory properties can have a negative influence on gene control, which seems to become most apparent during aging of cells when the repression of TES may be less effective. The careful dissection of the involvement of TEs and their partner KZNFs in several diseases can eventually lead to the development of therapeutic strategies in the future.