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Ofelia Karlsson- Institutionen för experimentell medicinsk vetenskap
Title: The Role of Heterochromatin in Human Brain Development
Main supervisor: Johan Jakobsson
Reviewers: Sofie Mohlin and Cristian Bellodi
Abstract
Transposable elements (TEs) are mobile genetic elements that throughout evolution have entered and colonized our genome by cutting or copying their sequence and inserting it into to a new genomic location. As a result, half of the human genome consists of TEs.
TEs can provide genetic diversity and serve as a machinery for evolution and speciation. In project 1, we identify a chimpanzee specific TE insertion in LINC00662, a long non-coding RNA exclusively expressed in human. This TE insertion results in loss of LINC00662 expression in chimpanzee stem cells, that can be restored by CRISPR-Cas9 mediated excision of the element. Functional analysis of LINC00662 in cerebral organoids revealed that it is an important regulator of genes involved in axon development, contributing to the establishment of a human specific transcriptional program.
It has further been speculated that TEs are co-opted by the host genome to diversify its function and modulate gene transcription. However, the mechanisms underlying such TE co-option is poorly understood. In project 2, we show that the RNA modification N6-methyladenosine (m6A) positively correlates with the expression of intronic TEs. The m6A modified elements can in turn influence the expression and processing of their hosting transcripts, showing a new layer of transcriptional regulation executed by TEs in human neural progenitor cells (hNPCs).
TEs can also cause a threat to the genomic integrity. To protect the host genome from mutagenic events and aberrant transcription, most TEs are transcriptionally silenced via epigenetic mechanisms such as DNA and histone methylation. In project 3, we investigate how loss of SETDB1 mediated heterochromatin affect TE expression in hNPCs. While DNA-methylation has been proposed as the main mechanism for TE silencing in human somatic cells, we found that loss of SETDB1 resulted in transcriptional activation of various families of TEs. These observations suggests that SETDB1 influences DNA methylation maintenance.
To profile molecular mechanisms governing TE activity is of great importance to better understand the healthy human brain and mechanisms underlying brain disorders. This thesis work provides further understanding on how TEs are regulated in neuronal cells and their impact on gene regulation, contributing to evolutionary processes.
Published studies
Garza, R., Atacho, D., Adami, A., Gerdes, P., Vinod, M., Hsieh, P., Karlsson, O., Horvath, V., Johansson, P.A., Pandiloski, N., Matas, J., Quaegebeur, A., Kouli, A., Sharma, Y., Jönsson, M. E., Monni, E., Englund, E., Eichler, E. E., Gale Hammel, M., Barker, R. A., Kokaia, Z., Douse, C. H., Jakobsson, J. (2023). L1 retrotransposons drive human neuronal transcriptome complexity and functional diversification. Science Advances, 9(44), eadh954
Pandiloski, N., Horvath, V., Karlsson, O., Christoforidou, G., Dorazehi, F., Koutounidou, S., Matas, J., Gerdes, P., Garza, R., Jönsson, M. E., Adami, A., Atacho, D., Johansson, J. G., Englund, E., Kokaia, Z., Jakobsson, J., Douse C. H. (2023) DNA methylation governs the sensitivity of repeats to restriction by the HUSH-MORC2 corepressor. BioRxiv (submitted, in revision)
Om evenemanget
Plats:
E11079 (Dialogen)
Kontakt:
ofelia [dot] karlsson [at] med [dot] lu [dot] se