RT Journal Article
SR Electronic
T1 Non-coding germline <em>GATA3</em> variants alter chromatin topology and contribute to pathogenesis of acute lymphoblastic leukemia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.23.961672
DO 10.1101/2020.02.23.961672
A1 Hongbo Yang
A1 Hui Zhang
A1 Yu Luan
A1 Tingting Liu
A1 Kathryn G Roberts
A1 Mao-xiang Qian
A1 Bo Zhang
A1 Wenjian Yang
A1 Virginia Perez-Andreu
A1 Jie Xu
A1 Sriranga Iyyanki
A1 Da Kuang
A1 Shalini C. Reshmi
A1 Julie Gastier-Foster
A1 Colton Smith
A1 Ching-Hon Pui
A1 William E Evans
A1 Stephen P Hunger
A1 Leonidas C. Platanias
A1 Mary V Relling
A1 Charles G Mullighan
A1 Mignon L Loh
A1 Feng Yue
A1 Jun J Yang
YR 2020
UL http://biorxiv.org/content/early/2020/02/25/2020.02.23.961672.abstract
AB 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.