Biology subjects

Luan, Y.

Publications and source records attributed to Luan, Y..

3 recordsLinked to original sources

bioRxiv2020

Subtype-specific epigenomic landscape and 3D genome structure in bladder cancer

Muscle-invasive bladder cancers have recently been characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. For example, FOXA1, GATA3, and PPARG have been shown to be essential for luminal subtype-specific regulation and subtype switching, while TP63 and STAT3 are critical for basal subtype bladder cancer. Despite these advances, the underlying epigenetic mechanism and 3D chromatin architecture for subtype-specific regulation in bladder cancers remains largely unknown. Here, we determined the genome-wide transcriptome, enhancer landscape, TF binding profiles (FOXA1 and GATA3) in luminal and basal subtypes of bladder cancers. Furthermore, we mapped genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors, for the first time in bladder cancer. We showed that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct TF binding at distal-enhancers of luminal and basal bladder cancers. Finally, we identified a novel clinically relevant transcriptional factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other luminal-specific genes (such as FOXA1, GATA3, and PPARG) and affects cancer cell proliferation and migration. In summary, our work shows a subtype-specific epigenomic and 3D genome structure in urinary bladder cancers and suggested a novel link between the circadian TF NPAS2 and a clinical bladder cancer subtype.

genomics↗

bioRxiv2020

Non-coding germline GATA3 variants alter chromatin topology and contribute to pathogenesis of acute lymphoblastic leukemia

Inherited non-coding genetic variants confer significant disease susceptibility in many cancers. However, the molecular processes of by which germline variants contribute to somatic lesions are poorly understood. We performed targeted sequencing in 5,008 patients and identified a key regulatory germline variant in GATA3 strongly associated with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). By creating an isogenic cellular model with CRISPR-Cas9 system, we showed that this variant activated a strong enhancer that significantly upregulated GATA3 transcription, which in turn reshaped the global chromatin accessibility and 3D genome organization. Remarkably, this genotype switch induced a chromatin loop between the CRLF2 oncogene and a distal enhancer, similar to the somatically acquired super-enhancer hijacking event in patients. GATA3 genotype-related alterations in transcriptional control and 3D chromatin organization were further validated in Ph-like ALL patients. Finally, we showed that GATA3 directly regulates CRLF2 and potentiates the oncogenic effects of JAK-STAT signaling in leukemogenesis. Altogether, our results provide evidence for a novel mechanism by which a germline non-coding variant contributes to oncogene activation epigenetic regulation and 3D genome reprogramming.

cancer biology↗

bioRxiv2019

Detection of genome-wide low-frequency mutations with Paired-End and Complementary Consensus Sequencing (PECC-Seq) revealed end-repair derived artifacts as residual errors

To improve the accuracy and the cost-efficiency of next-generation sequencing in ultralow-frequency mutation detection, we developed the Paired-End and Complementary Consensus Sequencing (PECC-Seq), a PCR-free duplex consensus sequencing approach. PECC-Seq employed shear points as endogenous barcodes to identify consensus sequences from the overlap in the shortened, complementary DNA strands-derived paired-end reads for sequencing error correction. With the high accuracy of PECC-Seq, we identified the characteristic base substitution errors introduced by the end-repair process of mechanical fragmentation-based library preparations, which were prominent at the terminal 6 bp of the library fragments in the 5-NpCpA-3 or 5-NpCpT-3 trinucleotide context. As demonstrated at the human genome scale (TK6 cells), after removing these potential end-repair artifacts from the terminal 6 bp, PECC-Seq could reduce the sequencing error frequency to mid-10-7 with a relatively low sequencing depth. For TA base pairs, the background error rate could be suppressed to mid-10-8. In mutagen-treated TK6, slight increases in mutagen treatment-related mutant frequencies could be detected, indicating the potential of PECC-Seq in detecting genome-wide ultra-rare mutations. In addition, our finding on the patterns of end-repair artifacts may provide new insights in further reducing technical errors not only for PECC-Seq, but also for other next-generation sequencing techniques.

genomics↗