Biology subjects

Pomella, S.

Publications and source records attributed to Pomella, S..

2 recordsLinked to original sources

bioRxiv2021

SNAI2-mediated direct repression of BIM protects rhabdomyosarcoma from ionizing radiation

Ionizing radiation (IR) and chemotherapy are the mainstays of treatment for patients with rhabdomyosarcoma (RMS). Yet, the molecular mechanisms that underlie the success or failure of radiotherapy remain unclear. The transcriptional repressor SNAI2 was previously identified as a key regulator of IR sensitivity in normal and malignant stem cells through its repression of the proapoptotic BH3-only gene PUMA. Here, we demonstrate a clear correlation between SNAI2 expression levels and radiosensitivity across multiple RMS cell lines. Moreover, modulating SNAI2 levels in RMS cells through its overexpression or knockdown can alter radiosensitivity in vitro and in vivo. SNAI2 expression reliably promotes overall cell growth and inhibits mitochondrial apoptosis following exposure to IR, with either variable or minimal effects on differentiation and senescence, respectively. Importantly, SNAI2 knockdown results in a striking increase in expression of the proapoptotic BH3-only gene BIM, and ChIP-seq experiments establish that SNAI2 is a direct repressor of BIM. Since the P53 pathway is nonfunctional in the RMS cells used in this study, we have identified a new, P53-independent SNAI2/BIM axis that could potentially predict clinical responses to IR treatment and be exploited to improve RMS therapy. HighlightsO_LISNAI2 expression levels are directly correlated with protection from radiation in rhabdomyosarcoma. C_LIO_LILoss of SNAI2 primes rhabdomyosarcomas for IR-induced apoptosis. C_LIO_LISNAI2 directly represses the expression of the proapoptotic BH3-only gene BIM. C_LI

cancer biology↗

bioRxiv2019

Miswired enhancer logic drives translocation positive rhabdomyosarcoma

Core regularity transcription factors (CR TFs) define cell identity and lineage through an exquisitely precise and logical order during embryogenesis and development. These CR TFs regulate one another in three-dimensional space via distal enhancers that serve as logic gates embedded in their TF recognition sequences. Aberrant chromatin organization resulting in miswired circuitry of enhancer logic is a newly recognized feature in many cancers. Here, we report that PAX3-FOXO1 expression is driven by a translocated FOXO1 distal super enhancer (SE). Using 4C-seq, a technique detecting all genomic regions that interact with the translocated FOXO1 SE, we demonstrate its physical interaction with the PAX3 promotor only in the presence of the oncogenic translocation. Furthermore, RNA-seq and ChIP-seq in tumors bearing rare PAX translocations implicate enhancer miswiring is a pervasive feature across all FP-RMS tumors. HiChIP of enhancer mark H3K27ac showed extended connectivity between the distal FOXO1 SE and additional intra-domain enhancers and the PAX3 promoter. We show by CRISPR-paired-ChIP-Rx that PAX3-FOXO1 transcription is diminished when this network of enhancers is selectively ablated. Therefore, our data reveal a mechanism of a translocated hijacked enhancer which disrupts the normal CR TF logic during skeletal muscle development (PAX3 to MYOD to MYOG), replacing it with an infinite loop logic that locks rhabdomyosarcoma cells in an undifferentiated proliferating stage.

cancer biology↗