Investigating the potential role of a human long non-coding RNA with ‘accelerated evolution’ in neurodevelopment and gliomas

Waters, Ella (2024). Investigating the potential role of a human long non-coding RNA with ‘accelerated evolution’ in neurodevelopment and gliomas. PhD thesis The Open University.



Long non-coding RNAs (lncRNAs) have a wide range of functions in health and disease, but many remain uncharacterised. Human accelerated region 1 (HAR1) and HAQER0035 are stretches of genomic DNA that, in humans, have significantly altered base sequences relative to chimpanzees. HAR1A and HAR1B are overlapping lncRNAs containing these sequences, and their expression has been shown to be regulated by the RE1 silencing transcription factor (REST). The functions of these lncRNAs are largely unknown, but they have been associated with neurodevelopment and neurological disorders. In cancers, low expression of HAR1A and HAR1B is correlated with glioma progression and poor patient prognosis.

The aim of this study was to characterise and investigate the role of HAR1A and HAR1B in the context of the healthy or diseased human nervous system. The expression patterns of HAR1A, HAR1B and REST were investigated in silico using a developing human brain and clinical glioma datasets, revealing an inverse correlation between the lncRNAs and REST. The expression of the lncRNAs increases postnatally, in structures relevant to memory and sensory processing, and their low expression correlates with advanced glioma grade and poor prognosis. Gene ontology analysis found the most enriched process associated with HAR1 expression to be chemical synaptic signalling.

Following the in silico analysis, the expression and function of HAR1A was analysed in a neural progenitor cell line (ReN VM) that could be readily differentiated into astrocytes and dopaminergic neurons, and in multiple brain cancer cell lines (U-373, SH-SY5Y, DIPGA, GIN28, GCE28). Key studies determined the subcellular localisation of HAR1Ato be nuclear. Upon ReN cell differentiation, the expression of HAR1Awas found to decrease within 12 hours, independent of the locus, though cell distribution did not change from baseline. HAR1Awas expressed via lentiviral overexpression, and its subcellular localisation confirmed to be retained in the nucleus. In ReN cells, proliferation, migration assays, KCl incubation and assessment of nuclear morphology by TEM identified little observable effect of HAR1A overexpression. In U-373 cells, HAR1A expression was increased with siRNA silencing of REST, but the reduction in cell proliferation observed was not correlated with HAR1A overexpression. Similar to ReN, little observable effect of HAR1Aoverexpression was found when analysing proliferation, migration and nuclear morphology.

This study has revealed that HAR1A is not involved in widely measured phenotypes, however, the rapid degradation associated with differentiation suggest that HAR1A plays a role in maintaining a less specialised, or early neuronal cell type.

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