FOXA1
Hepatocyte nuclear factor 3-alpha (HNF-3-alpha) (HNF-3A) (Forkhead box protein A1) (Transcription factor 3A) (TCF-3A) [HNF3A] [TCF3A]
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Forkhead box protein A1 ([i]FOXA1[/i]) is a pioneer factor of estrogen receptor α (ER)-chromatin binding and function, yet the role of [i]FOXA1[/i] in breast cancer and the underlying molecular mechanisms have not yet been elucidated. To evaluate gene expression alterations during breast carcinogenesis, [i]FOXA1[/i] expression was analyzed using the Serial Analysis of Gene Expression Genie suite, a gene expression profiling interactive analysis, and Oncomine analyses. The correlation between methylation and expression was analyzed using the MEXPRESS tool and UCSC Xena browser. Then, the expression and prognostic value of FOXA1 was validated by our own breast cancer samples using RT-PCR. We obtained the following important results. (1) The expression level of [i]FOXA1[/i] was significantly higher in breast cancer than normal tissues. (2) ER, PR, HEGR-2, and nodal status were positively correlated with [i]FOXA1[/i] expression. (3) Among patients with ER tumors, those with higher [i]FOXA1[/i] expression levels had better survival probabilities. (4) The major mutation type in [i]FOXA1[/i] in breast cancer samples was missense mutations. (5) [i]FOXA1[/i] expression was significantly higher in ER breast tumors than in ER- tumors or normal tissues. Our findings suggest that the aberrant DNA hypomethylation of promoter regions is one mechanism underlying the aberrant expression of [i]FOXA1[/i] in ER breast cancer, which might be a potential indicator of favorable prognosis.
MeSH Terms
- Breast Neoplasms
- Down-Regulation
- Epigenesis, Genetic
- Female
- Gene Expression Regulation, Neoplastic
- Hepatocyte Nuclear Factor 3-alpha
- Humans
- Middle Aged
- Prognosis
- RNA, Messenger
- Receptor, ErbB-2
- Receptors, Estrogen
- Receptors, Progesterone
- Transcriptome
- Up-Regulation
Keywords
- FOXA1
- age-related diseases
- aging
- breast cancer
- hormone receptor
- methylation
- prognosis
Copy number variations (CNVs) have been shown to cause numerous diseases, however, their roles in human lifespan remain elusive. In this study, we investigate the association of CNVs with longevity by comparing the Han Chinese genomes of long-lived individuals from 90 to 117 years of age and the middle-aged from 30 to 65. Our data demonstrate that the numbers of CNVs, especially deletions, increase significantly in a direct correlation with longevity. We identify eleven CNVs that strongly associate with longevity; four of them locate in the chromosome bands, 7p11.2, 20q13.33, 19p12 and 8p23.3 and overlap partially with the CNVs identified in long-lived Danish or U.S. populations, while the other seven have not been reported previously. These CNV regions encode nineteen known genes, and some of which have been shown to affect aging-related phenotypes such as the shortening of telomere length ([i]ZNF208[/i]), the risk of cancer ([i]FOXA1, LAMA5, ZNF716[/i]), and vascular and immune-related diseases ([i]ARHGEF10, [[TOR2A]], SH2D3C[/i]). In addition, we found several pathways enriched in long-lived genomes, including FOXA1 and FOXA transcription factor networks involved in regulating aging or age-dependent diseases such as cancer. Thus, our study has identified longevity-associated CNV regions and their affected genes and pathways. Our results suggest that the human genome structures such as CNVs might play an important role in determining a long life in human.
MeSH Terms
- Aged
- Aged, 80 and over
- Asian Continental Ancestry Group
- DNA Copy Number Variations
- Female
- Gene Expression Regulation
- Genome
- Genome-Wide Association Study
- Humans
- Longevity
- Male
Keywords
- Han Chinese
- copy number variation
- genome association study
- long-lived
- longevity
- middle-aged controls
The mammalian prostate is a compact structure in humans but multi-lobed in mice. In humans and mice, FOXA1 and SOX9 play pivotal roles in prostate morphogenesis, but few other species have been examined. We examined FOXA1 and SOX9 in the marsupial tammar wallaby, Macropus eugenii, which has a segmented prostate more similar to human than to mouse. In males, prostatic budding in the urogenital epithelium (UGE) was initiated by day 24 postpartum (pp), but in the female the UGE remained smooth and had begun forming the marsupial vaginal structures. FOXA1 was upregulated in the male urogenital sinus (UGS) by day 51 pp, whilst in the female UGS FOXA1 remained basal. FOXA1 was localised in the UGE in both sexes between day 20 and 80 pp. SOX9 was upregulated in the male UGS at day 21-30 pp and remained high until day 51-60 pp. SOX9 protein was localised in the distal tips of prostatic buds which were highly proliferative. The persistent upregulation of the transcription factors SOX9 and FOXA1 after the initial peak and fall of androgen levels suggest that in the tammar, as in other mammals, these factors are required to sustain prostate differentiation, development and proliferation as androgen levels return to basal levels.
MeSH Terms
- Aging
- Animals
- Female
- Gene Expression
- Hepatocyte Nuclear Factor 3-alpha
- Humans
- Immunohistochemistry
- Macropodidae
- Male
- Mice
- Polymerase Chain Reaction
- Proliferating Cell Nuclear Antigen
- Prostate
- SOX9 Transcription Factor
- Sex Characteristics
- Urogenital System
- Vagina
Expression levels of genes encoding specific transcription factors and other functionally important proteins vary upon aging of pancreatic and bronchial epithelium cell cultures. The peptides KEDW and AEDL tissue-specifically affect gene expression in pancreatic and bronchial cell cultures, respectively. It is established in this work that the DNA methylation patterns of the PDX1, PAX6, NGN3, NKX2-1, and SCGB1A1 gene promoter regions change upon aging in pancreatic and bronchial cell cultures in correlation with variations in their expression levels. Thus, stable changes in gene expression upon aging of cell cultures could be caused by changes in their promoter methylation patterns. The methylation patterns of the PAX4 gene in pancreatic cells as well as those of the FOXA1, SCGB3A2, and SFTPA1 genes in bronchial cells do not change upon aging and are unaffected by peptides, whereas their expression levels change in both cases. The promoter region of the FOXA2 gene in pancreatic cells contains a small number of methylated CpG sites, their methylation levels being affected by cell culture aging and KEDW, though without any correlation with gene expression levels. The promoter region of the FOXA2 gene is completely unmethylated in bronchial cells irrespective of cell culture age and AEDL action. Changes in promoter methylation might be the cause of age- and peptide-induced variations in expression levels of the PDX1, PAX6, and NGN3 genes in pancreatic cells and NKX2-1 and SCGB1A1 genes in bronchial cells. Expression levels of the PAX4 and FOXA2 genes in pancreatic cells and FOXA1, FOXA2, SCGB3A2, and SFTPA1 genes in bronchial cells seem to be controlled by some other mechanisms.
MeSH Terms
- Aging
- Cell Line
- Cellular Senescence
- DNA Methylation
- Epigenesis, Genetic
- Gene Expression Regulation
- Humans
- Peptides
- Promoter Regions, Genetic
Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels. Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity. Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Blood Glucose
- Chromosomes, Human, Pair 11
- Cohort Studies
- Death Domain Receptor Signaling Adaptor Proteins
- Diabetes Mellitus, Type 2
- Fasting
- Female
- Gene Frequency
- Genetic Variation
- Genome-Wide Association Study
- Genomics
- Guanine Nucleotide Exchange Factors
- Heart Diseases
- Humans
- Insulin
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Sequence Analysis, DNA
Keywords
- genetic epidemiology
- glucose
- human genetics
- insulin
- molecular genetics