Biology subjects

Tunbak, H.

Publications and source records attributed to Tunbak, H..

4 recordsLinked to original sources

bioRxiv2026

TEgment dissects transposable element reactivation upon CDK9 inhibition in acute myeloid leukemia

Cyclin-dependent kinase 9 (CDK9) inhibition represents a promising therapeutic strategy in cancers that disrupts RNA polymerase II pause release and collapses oncogenic transcripts. Here, we show that CDK9 inhibition also induces widespread transposable element (TE) activation across diverse cancer types. In acute myeloid leukemia (AML), CDK9 inhibition induces rapid epigenetic reprogramming and robust TE upregulation. To dissect this non-canonical transcriptional response, we developed TEgment, a TE-centric RNA-sequencing analysis pipeline that classifies TE expression into distinct structural modalities: standalone, readthrough, protein-coding gene-embedded (5'UTR, coding exons, and 3'UTRs), lncRNA-embedded, intron-retained, and TE-initiated/terminated transcription events. Applying TEgment to CDK9-inhibited AML revealed that TEs are predominantly expressed as readthrough, 3'UTR-embedded, and lncRNA-embedded transcripts rather than autonomous units, challenging prevailing assumptions about TE reactivation. TEgment provides a versatile framework for resolving TE transcriptional modalities at locus and structural levels, enabling precise interpretation of TE-derived transcripts in cancer and other contexts.

genomics↗

bioRxiv2022

Co-option of endogenous retroviruses through genetic escape from TRIM28 repression

Endogenous retroviruses (ERVs) have rewired host gene networks through co-option of their enhancers. To explore which ERVs get co-opted and why, we tracked the epigenetic fate of murine IAPEz elements using an in vitro model of embryonic stem cell (ESC) to neural progenitor cell (NPC) differentiation. TRIM28-repression depended on a 190bp sequence, previously shown to confer IAPEzs with retrotransposition activity. A subset of IAPEzs ([~]15%) exhibit genetic divergence from this sequence, which we term escapees. While repressed IAPEzs succumb to a previously undocumented epigenetic handover from H3K9me3 in ESCs to H3K27me3 in NPCs, escapee IAPEzs evade repression, resulting in their transcriptional derepression in NPCs. Escapee IAPEzs enhance expression of nearby neural genes and contribute to gene expression differences between mouse strains, which we discern by employing IAPEz insertion polymorphisms. In sum, co-opted ERVs stem from genetic escapees that have lost vital sequences required for both TRIM28 restriction and autonomous retrotransposition. HIGHLIGHTSO_LITracking the epigenetic fate of ERVs through neural differentiation reveals which ERVs are subject to co-option and why. C_LIO_LIMost ERVs succumb to H3K9me3 deposition in ESCs with H3K27me3 memory in NPCs. C_LIO_LIERVs that act as enhancers to nearby neural genes have undergone genetic escape from TRIM28 repression. C_LIO_LIEpigenetic evasion is an evolutionary trade-off that comes with loss of sequences necessary for retrotransposition. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/497016v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@175b6c0org.highwire.dtl.DTLVardef@1313692org.highwire.dtl.DTLVardef@1f5e33forg.highwire.dtl.DTLVardef@1a5ad3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO C_FIG

molecular biology↗

bioRxiv2020

A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes

Hundreds of human genes are associated with neurological diseases, but translation into tractable biological mechanisms is lagging. Larval zebrafish are an attractive model to investigate genetic contributions to neurological diseases. However, current CRISPR-Cas9 methods are difficult to apply to large genetic screens studying behavioural phenotypes. To facilitate rapid genetic screening, we developed a simple sequencing-free tool to validate gRNAs and a highly effective CRISPR-Cas9 method capable of converting >90% of injected embryos directly into F0 biallelic knockouts. We demonstrate that F0 knockouts reliably recapitulate complex mutant phenotypes, such as altered molecular rhythms of the circadian clock, escape responses to irritants, and multi-parameter day-night locomotor behaviours. The technique is sufficiently robust to knockout multiple genes in the same animal, for example to create the transparent triple knockout crystal fish for imaging. Our F0 knockout method cuts the experimental time from gene to behavioural phenotype in zebrafish from months to one week.

genetics↗

bioRxiv2020

The lonely fish is not a loner fish: whole-brain mapping reveals abnormal activity in socially isolated zebrafish

The zebrafish is used to assess the impact of social isolation on behaviour and brain function. As in humans and other social species, early social deprivation reduces social preference in juvenile zebrafish. Whole-brain functional maps of anti-social isolated fish were distinct from anti-social fish found in the normal population. These isolation-induced activity changes revealed profound disruption of neural activity in brain areas linked to social behaviour, such as the preoptic area and hypothalamus. Several of these affected regions are modulated by serotonin, and we found that social preference in isolated fish could be rescued by acutely reducing serotonin levels.

neuroscience↗