Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers
NATURE GENETICS
Authors: Zhang, Xiaoyang; Choi, Peter S.; Francis, Joshua M.; Imielinski, Marcin; Watanabe, Hideo; Cherniack, Andrew D.; Meyerson, Matthew
Abstract
Whole-genome analysis approaches are identifying recurrent cancer-associated somatic alterations in noncoding DNA regions. We combined somatic copy number analysis of 12 tumor types with tissue-specific epigenetic profiling to identify significant regions of focal amplification harboring super-enhancers. Copy number gains of noncoding regions harboring super-enhancers near KLF5, USP12, PARD6B and MYC are associated with overexpression of these cancer-related genes. We show that two distinct focal amplifications of super-enhancers 3' to MYC in lung adenocarcinoma (MYC-LASE) and endometrial carcinoma (MYC-ECSE) are physically associated with the MYC promoter and correlate with MYC overexpression. CRISPR/Cas9-mediated repression or deletion of a constituent enhancer within the MYC-LASE region led to significant reductions in the expression of MYC and its target genes and to the impairment of anchorage independent and clonogenic growth, consistent with an oncogenic function. Our results suggest that genomic amplification of super-enhancers represents a common mechanism to activate cancer driver genes in multiple cancer types.
Identification of biomarker candidates for fertility in spermatozoa of crossbred bulls through comparative proteomics
THERIOGENOLOGY
Authors: Aslam, M. K. Muhammad; Sharma, Vinay K.; Pandey, Shashank; Kumaresan, A.; Srinivasan, A.; Datta, T. K.; Mohanty, T. K.; Yadav, Savita
Abstract
Associations between expression of some proteins in spermatozoa and fertility have been sought in recent years to identify the male fertility markers. Since the incidence of sub-fertility is high in crossbred bulls, the present investigation was carried out on high- and low-fertile crossbred bulls to identify fertility markers in spermatozoa through proteomics approach. Sperm proteome of high-fertile bulls were compared with low-fertile bulls using 2D-DIGE and MALDI-TOF-MS techniques and the results were validated with immuno-blotting. The proteins MDH2, ENO1, RIBCI, CAPN7, ATP5D, LacA like protein-2 like, NCAPD3, DECRI, GCNT2, GDI2, TOP and USP12 were over expressed in high-fertile spermatozoa, whereas DST like isoform 1, TMEM43 and BSPI were over expressed in low-fertile spermatozoa (P < 0.05). The differential expression ranged from 1.57 (GDI2) to 5.1 (BSP1) fold between the two groups. Based on the GO annotation, majority of them were involved in cellular and metabolic processes, with catalytic and binding activities, and localized in cell and organelles. Among these proteins, ENO1 and BSPI were selected based on the degree of differential expression and reliability in identification, for further validation. Immuno-blotting studies indicated that ENO1 expression was positively correlated (P < 0.05) while the expression of BSPI was negatively (P < 0.01) correlated with bull fertility. The proportion of capacitated spermatozoa in frozen thawed spermatozoa of low-fertile bulls was higher (P < 0.05) as compared to high-fertile bulls. Collectively, the study identified some potential molecules in spermatozoa of bulls, which may act as a panel of biomarkers for fertility. (C) 2018 Elsevier Inc. All rights reserved.