Biology subjects

Songyang, Z.

Publications and source records attributed to Songyang, Z..

3 recordsLinked to original sources

bioRxiv2026

Pan-cancer silencer transcription atlas reveals leukemia silencer hijacking FOXP1 to enhance MYC oncogene

Numerous non-coding regulatory elements have been identified in the human genome. However, our understanding of silencers remains largely incomplete. Here, we proposed the concept of silencer transcriptional activity (STA) to investigated silencers from a new perspective using >20,000 transcriptomes. We demonstrated that lower STAs predicted better patient outcomes in most cancers, and a subset of STAs distinguished tumors from noncancerous tissues for most cancer types. Importantly, we discovered a silencer-linked RNA (slRNA) of a leukemia cell-specific silencer (LeSSi). Knocking down (KD) of the slRNA significantly decreased leukemia cell viability and migration and increased cellular apoptosis. Furthermore, the direct link and functional similarity between LeSSi and slRNA were established by CRISPR/Cas9 knocking out (KO) of LeSSi. Mechanistically, the slRNA hijacked FOXP1, which functions here both as a known transcription factor (TF), and more importantly, as a novel RNA binding protein (RBP), thereby preventing FOXP1 from binding to the promoter of proto-oncogene MYC and subsequently promoting MYC transcription. Collectively, our work provides insights into the functions of silencers in cancer and identified a slRNA hijacking FOXP1 to enhance MYC expression in leukemia cells.

genomics↗

bioRxiv2022

Identifying new regulators of evolutionarily conserved differential chromosome X dosage compensation

The active X chromosome in mammals is upregulated to balance its dosage to autosomes during evolution. However, it is elusive why the currently known dosage compensation machinery showed uneven and small influence on X genes, necessitating systemic investigation of X dosage in different angles and identification of new dosage regulators. Here, based on >20,000 transcriptomes, we identified two X gene groups (genome ploidy-sensitive [PSX] and ploidy-insensitive [PIX] genes), showing distinct but evolutionarily-conserved (in both primates and mouse) dosage compensations (termed X-over-Autosome dosage Ratio, or XAR). We then explored XAR in diseases and in stem cells, where XAR is potentially important. We demonstrated that XAR-PIX was downregulated while XAR-PSX upregulated across cancer types at both RNA and protein levels. In contrast, XAR-PIX was upregulated while XAR-PSX downregulated during stem cell differentiation. Interestingly, XAR-PIX, but not XAR-PSX, was significantly lower and associated with autoantibodies and inflammation in lupus patients, suggesting that insufficient dosage of PIX genes may contribute to lupus pathogenesis. We further identified and experimentally validated two new XAR regulators, TP53 and ATRX. Collectively, we provided insights to further unravel the mystery of X dosage compensation in mammals and its pathophysiological roles in human diseases.

cancer biology↗

bioRxiv2020

A synergistic action of sirtuins directly recognizes DNA breaks and potentiates DNA damage response and repair

The DNA damage response (DDR) is a highly orchestrated process but how double-strand DNA breaks (DSBs) are initially recognized is unclear. Here, we show that polymerized SIRT6 deacetylase recognizes DSBs and potentiates the DDR. First, SIRT1 deacetylates SIRT6 at residue K33, which is important for SIRT6 polymerization and mobilization toward DSBs. Then, K33-deacetylated SIRT6 anchors to {gamma}H2AX, allowing its retention on and subsequent remodeling of local chromatin. We show that a K33R mutation that mimics hypoacetylated SIRT6 can rescue defective DNA repair as a result of SIRT1 deficiency in cultured cells. These data highlight the synergistic action between SIRTs in the spatiotemporal regulation of the DDR and DNA repair.

biochemistry↗