Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A, formerly known as PGC-1a) is a transcriptional coactivator and metabolic regulator. Previous studies are mainly focused on the association between PPARGC1A and hepatoma. However, the regulatory mechanism remains unknown. A microRNA associated with cancer (oncomiR), miR-93-5p, has recently been found to play an essential role in tumorigenesis and progression of various carcinomas, including liver cancer. Therefore, this paper aims to explore the regulatory mechanism underlying these two proteins in hepatoma cells. Firstly, an integrative analysis was performed with miRNA–mRNA modules on microarray and The Cancer Genome Atlas (TCGA) data and obtained the core regulatory network and miR-93-5p/PPARGC1A pair. Then, a series of experiments were conducted in hepatoma cells with the results including miR-93-5p upregulated and promoted cell proliferation. Thirdly, the inverse correlation between miR-93-5p and PPARGC1A expression was validated. Finally, we inferred that miR-93-5p plays an essential role in inhibiting PPARGC1A expression by directly targeting the 3′-untranslated region (UTR) of its mRNA. In conclusion, these results suggested that miR-93-5p overexpression contributes to hepatoma development by inhibiting PPARGC1A. It is anticipated to be a promising therapeutic strategy for patients with liver cancer in the future.
The Dishevelled/EGL-10/Pleckstrin (DEP) domain-containing (DEPDC) proteins have seven members. However, whether this superfamily can be distinguished from other proteins based only on the amino acid sequences, remains unknown. Here, we describe a computational method to segregate DEPDCs and non-DEPDCs. First, we examined the Pfam numbers of the known DEPDCs and used the longest sequences for each Pfam to construct a phylogenetic tree. Subsequently, we extracted 188-dimensional (188D) and 20D features of DEPDCs and non-DEPDCs and classified them with random forest classifier. We also mined the motifs of human DEPDCs to find the related domains. Finally, we designed experimental verification methods of human DEPDC expression at the mRNA level in hepatocellular carcinoma (HCC) and adjacent normal tissues. The phylogenetic analysis showed that the DEPDCs superfamily can be divided into three clusters. Moreover, the 188D and 20D features can both be used to effectively distinguish the two protein types. Motif analysis revealed that the DEP and RhoGAP domain was common in human DEPDCs, human HCC and the adjacent tissues that widely expressed DEPDCs. However, their regulation was not identical. In conclusion, we successfully constructed a binary classifier for DEPDCs and experimentally verified their expression in human HCC tissues.
Estrogen receptor α (ERα) drives growth in the majority of human breast cancers by binding to regulatory elements and inducing transcriptional events that promote tumor growth. ERα binding activity largely depends on access to binding sites on chromatin, which is facilitated in part by Pioneer Factors (PFs). Transcription factors operate in complexes through thousands of genomic binding sites in a combinatorial fashion to control the expression of genes. However, the extent of crosstalk and cooperation between ERα pioneer factors and more collaborative transcription factors in breast cancer still remains to be elucidated systematically.Methods: Here, we determined the genomic binding information of 40 transcription-related factors and histone modifications with ChIP-seq in ENCODE and integrated it with other genomic information (RNA-seq, ATAC-seq, Gene microarray, 450k methylation chip, GRO-seq), forming a multi-dimension network to illuminate ERα associated transcription.Results: We show that transcription factor, NR2F2 binds to most sites independently of estrogen. Perturbation of NR2F2 expression decreases ERα DNA binding, chromatin openning, and estrogen-dependent cell growth. In the genome-wide analysis, we show that most binding events of NR2F2 and known pioneer factors FOXA1, GATA3 occur together, covering 85% of the ERα binding sites. Regions bound by all the three TFs appeared to be the most active, to have the strongest ERα binding and to be enriched for the super enhancers.Conclusions: The ERα binds to pre-accessible sites containing ERE elements bound by the three transcription factors (NR2F2, FOXA1 and GATA3).The three genes were also identified to correlate with decreased metastatic potential in patient cohorts and co-regulate each other. Together, our results suggest that NR2F2 is a cofactor with FOXA1 and GATA3 in ERα-mediated transcription.
Einkorn wheat (Triticum monococcum) is one of the oldest cereal crops to be domesticated by human beings, playing essential role in early agriculture development. Today, it is considered an important genomic resource for modern wheat improvement, especially for resistance against pests and diseases. However, the exploration and utilization of useful genes from T. monococcum is limited due to the lack of a reference genome and annotation for this species. Here, we report a near-complete genome assembly for T. monococcum with a total length of 5.11 Gb with a contig N50 of 131.2Mb and scaffold N50 of 728.66Mb, representing a genome assembly of highest quality for any wheat genome reported. Phylogenomic analysis confirmed T. monococcum is closely-related to T. urartu, the progenitor of wheat A subgenomes. A 4AL/5AL terminal translocation is present in the diploid species T. urartu and T. monococcum, taking place before wheat polyploidization. T. monococcum has significantly expanded and unique gene families involved in DNA damage repair and heat stress tolerance, reflecting its adaptive evolution to cope with historical harsh climate in its natural habitat, South East Turkey. The genome sequence confirmed the introgression of T. monococcum rust resistance genes at 5AmL into modern bread wheat varieties. This near-complete reference genome of T. monococcum will be an essential resource for wheat functional and evolutionary genomic studies and expedite the cloning of useful genes in T. monococcum for future wheat improvement. Keywords: Triticum monococcum, reference genome, genome rearrangement, resistance genes, stem and leaf rust, PacBio HiFi sequencing
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