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Patel, Chirag; Ghiselli, Giancarlo

doi:10.1186/1471-2121-6-3

Cited by 11 publications

(6 citation statements)

References 20 publications

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“…The deletion was supported by both the CNA and SV data, and it primarily affected a part of KIAA1328 , but also an intergenic region between KIAA1328 and the adjacent gene, CELF4 . KIAA1328 encodes a protein called hinderin, which has been shown to bind to SMC3, a subunit of the cohesin complex, which plays an important role in mediating sister chromatid cohesion, homologous recombination, and DNA looping [ 40 ]. Currently, there are no functional data available for the lncRNA (AC015961.1) or cCRE that are located in the intergenic region affected by the deletion.…”

Section: Discussionmentioning

confidence: 99%

“…Chromosome mapping was performed for chromosomes marked with an asterisk. P, primary tumor; M, metastasis complex, which plays an important role in mediating sister chromatid cohesion, homologous recombination, and DNA looping [40]. Currently, there are no functional data available for the lncRNA (AC015961.1) or cCRE that are located in the intergenic region affected by the deletion.…”

Section: Discussionmentioning

confidence: 99%

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Whole genome sequencing reveals the independent clonal origin of multifocal ileal neuroendocrine tumors

et al. 2022

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Background Small intestinal neuroendocrine tumors (SI-NETs) are the most common neoplasms of the small bowel. The majority of tumors are located in the distal ileum with a high incidence of multiple synchronous primary tumors. Even though up to 50% of SI-NET patients are diagnosed with multifocal disease, the mechanisms underlying multiple synchronous lesions remain elusive. Methods We performed whole genome sequencing of 75 de-identified synchronous primary tumors, 15 metastases, and corresponding normal samples from 13 patients with multifocal ileal NETs to identify recurrent somatic genomic alterations, frequently affected signaling pathways, and shared mutation signatures among multifocal SI-NETs. Additionally, we carried out chromosome mapping of the most recurrent copy-number alterations identified to determine which parental allele had been affected in each tumor and assessed the clonal relationships of the tumors within each patient. Results Absence of shared somatic variation between the synchronous primary tumors within each patient was observed, indicating that these tumors develop independently. Although recurrent copy-number alterations were identified, additional chromosome mapping revealed that tumors from the same patient can gain or lose different parental alleles. In addition to the previously reported CDKN1B loss-of-function mutations, we observed potential loss-of-function gene alterations in TNRC6B, a candidate tumor suppressor gene in a small subset of ileal NETs. Furthermore, we show that multiple metastases in the same patient can originate from either one or several primary tumors. Conclusions Our study demonstrates major genomic diversity among multifocal ileal NETs, highlighting the need to identify and remove all primary tumors, which have the potential to metastasize, and the need for optimized targeted treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing reveals the independent clonal origin of multifocal ileal neuroendocrine tumors

et al. 2022

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“…Hinge domains contribute to formation of a V-shaped SMC heterodimer [10], [11], [12], and may be a target of regulatory factors [13], [14]. Hinge-mediated heterodimerization of SMC1 and SMC3 appears to be very stable, for isolated hinge dimers resist high salt and considerable detergent such as 0.01% SDS [15].…”

Section: Introductionmentioning

confidence: 99%

Imbalance of SMC1 and SMC3 Cohesins Causes Specific and Distinct Effects

et al. 2013

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SMC1 and SMC3 form a high-affinity heterodimer, which provides an open backbone of the cohesin ring, to be closed by a kleisin protein. RNAi mediated knock-down of either one heterodimer partner, SMC1 or SMC3, is expected to cause very similar if not identical phenotypes. However, we observed highly distinct, protein-specific phenotypes. Upon knock-down of human SMC1, much of SMC3 remains stable, accumulates in the cytoplasm and does not associate with other cohesin proteins. Most of the excess nuclear SMC3 is highly mobile and not or only weakly chromosome-associated. In contrast, human SMC3 knock-down rendered SMC1 instable without cytoplasmic accumulation. As observed by differential protein extraction and in FRAP experiments the remaining SMC1 or SMC3 proteins in the respective SMC1 or SMC3 knock-down experiments constituted a cohesin pool, which is associated with chromatin with highest affinity, likely the least expendable. Expression of bovine EGFP-SMC1 or mouse EGFP-SMC3 in human cells under conditions of human SMC1 or SMC3 knock-down rescued the respective phenotypes, but in untreated cells over-expressed exogenous SMC proteins mis-localized. Paucity of either one of the SMC proteins causes RAD21 degradation. These results argue for great caution in interpreting SMC1 and SMC3 RNAi or over-expression experiments. Under challenged conditions these two proteins unexpectedly behave differently, which may have biological consequences for regulation of cohesin-associated functions and for human cohesin pathologies.

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“…The significant alternative splicing identified in the TG for AW554918 was characterized by the under-expression of a transcript isoform that extends across two 3 exons in OIH relative to control mice (Figure 2, Table 3). The excision of the AW554918 transcript results in nonsense mediated decay or processed transcript that alters the abundance and activity of the encoded protein [80]. A shortened AW554918 transcript isoform may affect the availability of the hinderin (Kiaa1328) protein to engage in the formation of multimeric protein complexes [80].…”

Section: Relative Differential Expression Of Transcript Isoforms Associated With Opioid-induced Hyperalgesia In the Trigeminal Gangliamentioning

confidence: 99%

“…The excision of the AW554918 transcript results in nonsense mediated decay or processed transcript that alters the abundance and activity of the encoded protein [80]. A shortened AW554918 transcript isoform may affect the availability of the hinderin (Kiaa1328) protein to engage in the formation of multimeric protein complexes [80]. Cacna2d1 presented relative differential isoform expression in the TG and the change in the proportion of two transcripts between OIH and control mice presented opposite patterns (P-value < 0.003, Supplementary Table S3).…”

Section: Relative Differential Expression Of Transcript Isoforms Associated With Opioid-induced Hyperalgesia In the Trigeminal Gangliamentioning

confidence: 99%

Alternative Splicing Mechanisms Underlying Opioid-Induced Hyperalgesia

Zhang

Perez

Southey

et al. 2021

Genes

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Prolonged use of opioids can cause opioid-induced hyperalgesia (OIH). The impact of alternative splicing on OIH remains partially characterized. A study of the absolute and relative modes of action of alternative splicing further the understanding of the molecular mechanisms underlying OIH. Differential absolute and relative isoform profiles were detected in the trigeminal ganglia and nucleus accumbens of mice presenting OIH behaviors elicited by chronic morphine administration relative to control mice. Genes that participate in glutamatergic synapse (e.g., Grip1, Grin1, Wnk3), myelin protein processes (e.g., Mbp, Mpz), and axon guidance presented absolute and relative splicing associated with OIH. Splicing of genes in the gonadotropin-releasing hormone receptor pathway was detected in the nucleus accumbens while splicing in the vascular endothelial growth factor, endogenous cannabinoid signaling, circadian clock system, and metabotropic glutamate receptor pathways was detected in the trigeminal ganglia. A notable finding was the prevalence of alternatively spliced transcription factors and regulators (e.g., Ciart, Ablim2, Pbx1, Arntl2) in the trigeminal ganglia. Insights into the nociceptive and antinociceptive modulatory action of Hnrnpk were gained. The results from our study highlight the impact of alternative splicing and transcriptional regulators on OIH and expose the need for isoform-level research to advance the understanding of morphine-associated hyperalgesia.

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Cited by 11 publications

References 20 publications

Whole genome sequencing reveals the independent clonal origin of multifocal ileal neuroendocrine tumors

Whole genome sequencing reveals the independent clonal origin of multifocal ileal neuroendocrine tumors

Imbalance of SMC1 and SMC3 Cohesins Causes Specific and Distinct Effects

Alternative Splicing Mechanisms Underlying Opioid-Induced Hyperalgesia

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