RESUMEN
9p21 locus is one of the most reproducible regions in genome-wide association studies (GWAS). The region harbors CDKN2A/B genes that code for p16INK4a, p15INK4b, and p14ARF proteins, and it also harbors a long gene desert adjacent to these genes. The polymorphisms that are associated with several diseases and cancers are present in these genes and the gene desert region. These proteins are critical cell cycle regulators whose transcriptional dysregulation is strongly linked with cellular regeneration, stemness, aging, and cancers. Given the importance of this locus, intense scientific efforts on understanding the regulation of these genes via promoter-driven mechanisms and recently, via the distal regulatory mechanism have provided major insights. In this review, we describe these mechanisms and propose the ways by which this locus can be targeted in pathologies and aging.
RESUMEN
The genetic mechanisms underlying cutaneous melanoma onset and progression need to be further understood to improve patients' care. Several studies have focused on the genetic determinism of melanoma development in the MeLiM pig, a biomedical model of cutaneous melanoma. The objective of this study was to better describe the influence of a particular genomic region on melanoma progression in the MeliM model. Indeed, a large region of the Sus scrofa chromosome 1 has been identified by linkage and association analyses, but the causal mechanisms have remained elusive. To deepen the analysis of this candidate region, a dedicated SNP panel was used to fine map the locus, downsizing the interval to less than 2 Mb, in a genomic region located within a large gene desert. Transcription from this locus was addressed using a tiling array strategy and further validated by RT-PCR in a large panel of tissues. Overall, the gene desert showed an extensive transcriptional landscape, notably dominated by repeated element transcription in tumor and fetal tissues. The transcription of LINE-1 and PERVs has been confirmed in skin and tumor samples from MeLiM pigs. In conclusion, although this study still does not identify a candidate mutation for melanoma occurrence or progression, it highlights a potential role of repeated element transcriptional activity in the MeLiM model.
Asunto(s)
Cromosomas de los Mamíferos/genética , Perfilación de la Expresión Génica/veterinaria , Elementos de Nucleótido Esparcido Largo , Melanoma/genética , Polimorfismo de Nucleótido Simple , Neoplasias Cutáneas/genética , Animales , Mapeo Cromosómico , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Sus scrofa , Porcinos , Melanoma Cutáneo MalignoRESUMEN
FAM84B is a risk gene in breast and prostate cancers. Its upregulation is associated with poor prognosis of prostate cancer, breast cancer, and esophageal squamous cell carcinoma. FAM84B facilitates cancer cell proliferation and invasion in vitro, and xenograft growth in vivo. The FAM84B and Myc genes border a 1.2 Mb gene desert at 8q24.21. Co-amplification of both occurs in 20 cancer types. Mice deficient of a 430 Kb fragment within the 1.2 Mb gene desert have downregulated FAM84B and Myc expressions concurrent with reduced breast cancer growth. Intriguingly, Myc works in partnership with other oncogenes, including Ras. FAM84B shares similarities with the H-Ras-like suppressor (HRASLS) family over their typical LRAT (lecithin:retinal acyltransferase) domain. This domain contains a catalytic triad, H23, H35, and C113, which constitutes the phospholipase A1/2 and O-acyltransferase activities of HRASLS1-5. These enzymatic activities underlie their suppression of Ras. FAM84B conserves H23 and H35 but not C113 with both histidine residues residing within a highly conserved motif that FAM84B shares with HRASLS1-5. Deletion of this motif abolishes FAM84B oncogenic activities. These properties suggest a collaboration of FAM84B with Myc, consistent with the role of the gene desert in strengthening Myc functions. Here, we will discuss recent research on FAM84B-derived oncogenic potential.
Asunto(s)
Proliferación Celular/genética , Cromosomas Humanos Par 8/genética , Proteínas de la Membrana/genética , Proteínas de Neoplasias/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patologíaRESUMEN
Facultative heterochromatin forms and reorganizes in response to external stimuli. However, how the initial establishment of such a chromatin state is regulated in cell-cycle-arrested cells remains unexplored. Mouse gonocytes are arrested male germ cells, at which stage the genome-wide DNA methylome forms. Here, we discovered transiently accessible heterochromatin domains of several megabases in size in gonocytes and named them differentially accessible domains (DADs). Open DADs formed in gene desert and gene cluster regions, primarily at transposons, with the reprogramming of histone marks, suggesting DADs as facultative heterochromatin. De novo DNA methylation took place with two waves in gonocytes: the first region specific and the second genome-wide. DADs were resistant to the first wave and their opening preceded the second wave. In addition, the higher-order chromosome architecture was reorganized with less defined chromosome compartments in gonocytes. These findings suggest that multiple layers of chromatin reprogramming facilitate de novo DNA methylation.
Asunto(s)
Metilación de ADN , Células Germinativas/química , Heterocromatina/química , Testículo/embriología , Animales , Ciclo Celular , Cromatina/química , Cromosomas , Genoma , Histonas/química , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
AIMS: The integration preferences of human papillomavirus (HPV) have been intensively studied and contested over recent years. To disclose the integration preferences of high-risk HPV in cervical cancer, HPV transcriptional sites and features in different cervical cancer cell lines were identified. MAIN METHODS: In this study, three cervical cancer cell lines (CaSki, HeLa, and SiHa) were subjected for HPV genome status determination by amplification of papillomavirus oncogene transcripts (APOT) assay. The numbers of viral copies in human genomes and numbers of viral-human fusion mRNAs in three HPV-integrated cervical cancer cell lines were measured and analysed. KEY FINDINGS: The results revealed that the gene desert region 8q24 of the HPV type 18 integrated HeLa cell line and the 13q21-22 region of the HPV type 16 integrated CaSki and SiHa cell lines were hotspots for HPV integration, and the numbers of viral copies in the human genomes of the three cell lines that we detected were not in accordance with those reported in previous studies. SIGNIFICANCE: Integration of the HPV genome into the host cell chromosome suggests that persistent HPV infection is vital for malignant cell transformation and carcinogenesis. This study provides information to benefit health care professionals seeking more comprehensive and accurate diagnostics for HPV-related disease"? Please check, and amend as necessary.
Asunto(s)
Línea Celular Tumoral , Genoma Viral/genética , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Neoplasias del Cuello Uterino/genética , Integración Viral/genética , Femenino , Dosificación de Gen , Regulación Viral de la Expresión Génica/genética , Células HeLa , Humanos , ARN Viral/genética , Sitio de Iniciación de la TranscripciónRESUMEN
Colorectal cancer (CRC) has an apparent hereditary component, as evidenced by the well-characterized genetic syndromes and family history associated with the increased risk of this disease. However, in a large fraction of CRC cases, no known genetic syndrome or family history can be identified, suggesting the presence of "missing heritability" in CRC etiology. The genome-wide association study (GWAS) platform has led to the identification of multiple replicable common genetic variants associated with CRC risk. These newly discovered genetic variations might account for a portion of the missing heritability. Here, we summarize the recent GWASs related to newly identified genetic variants associated with CRC risk and clinical outcome. The findings from these studies suggest that there is a lack of understanding of the mechanism of many single nucleotide polymorphisms (SNPs) that are associated with CRC. In addition, the utility of SNPs as prognostic markers of CRC in clinical settings remains to be further assessed. Finally, the currently validated SNPs explain only a small fraction of total heritability in complex-trait diseases like CRC. Thus, the "missing heritability" still needs to be explored further. Future epidemiological and functional investigations of these variants will add to our understanding of CRC pathogenesis, and may ultimately lead to individualized strategies for prevention and treatment of CRC.