scholarly journals 16p11.2 transcription factor MAZ is a dosage-sensitive regulator of genitourinary development

2018 ◽  
Vol 115 (8) ◽  
pp. E1849-E1858 ◽  
Author(s):  
Meade Haller ◽  
Jason Au ◽  
Marisol O’Neill ◽  
Dolores J. Lamb
Keyword(s):  
Transcription Factor ◽  
Birth Defects ◽  
Copy Number ◽  
Congenital Malformations ◽  
Survival Rates ◽  
Hek293 Cells ◽  
High Morbidity ◽  
Cell Cycle Regulators ◽  
Human Embryonic Kidney Cells ◽  
Normal Bladder

Genitourinary (GU) birth defects are among the most common yet least studied congenital malformations. Congenital anomalies of the kidney and urinary tract (CAKUTs) have high morbidity and mortality rates and account for ∼30% of structural birth defects. Copy number variation (CNV) mapping revealed that 16p11.2 is a hotspot for GU development. The only gene covered collectively by all of the mapped GU-patient CNVs was MYC-associated zinc finger transcription factor (MAZ), and MAZ CNV frequency is enriched in nonsyndromic GU-abnormal patients. Knockdown of MAZ in HEK293 cells results in differential expression of several WNT morphogens required for normal GU development, including Wnt11 and Wnt4. MAZ knockdown also prevents efficient transition into S phase, affects transcription of cell-cycle regulators, and abrogates growth of human embryonic kidney cells. Murine Maz is ubiquitously expressed, and a CRISPR-Cas9 mouse model of Maz deletion results in perinatal lethality with survival rates dependent on Maz copy number. Homozygous loss of Maz results in high penetrance of CAKUTs, and Maz is haploinsufficient for normal bladder development. MAZ, once thought to be a simple housekeeping gene, encodes a dosage-sensitive transcription factor that regulates urogenital development and contributes to both nonsyndromic congenital malformations of the GU tract as well as the 16p11.2 phenotype.

scholarly journals Systematic analysis of copy number variation associated with congenital diaphragmatic hernia

2018 ◽  
Vol 115 (20) ◽  
pp. 5247-5252 ◽  
Author(s):  
Qihui Zhu ◽  
Frances A. High ◽  
Chengsheng Zhang ◽  
Eliza Cerveira ◽  
Meaghan K. Russell ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Candidate Genes ◽  
Birth Defects ◽  
Diaphragmatic Hernia ◽  
Copy Number ◽  
Large Scale ◽  
De Novo ◽  
Comparative Genomic ◽  
High Morbidity ◽  
Systematic Analysis

Congenital diaphragmatic hernia (CDH), characterized by malformation of the diaphragm and hypoplasia of the lungs, is one of the most common and severe birth defects, and is associated with high morbidity and mortality rates. There is growing evidence demonstrating that genetic factors contribute to CDH, although the pathogenesis remains largely elusive. Single-nucleotide polymorphisms have been studied in recent whole-exome sequencing efforts, but larger copy number variants (CNVs) have not yet been studied on a large scale in a case control study. To capture CNVs within CDH candidate regions, we developed and tested a targeted array comparative genomic hybridization platform to identify CNVs within 140 regions in 196 patients and 987 healthy controls, and identified six significant CNVs that were either unique to patients or enriched in patients compared with controls. These CDH-associated CNVs reveal high-priority candidate genes including HLX, LHX1, and HNF1B. We also discuss CNVs that are present in only one patient in the cohort but have additional evidence of pathogenicity, including extremely rare large and/or de novo CNVs. The candidate genes within these predicted disease-causing CNVs form functional networks with other known CDH genes and play putative roles in DNA binding/transcription regulation and embryonic development. These data substantiate the importance of CNVs in the etiology of CDH, identify CDH candidate genes and pathways, and highlight the importance of ongoing analysis of CNVs in the study of CDH and other structural birth defects.

scholarly journals Lessons Learned from CNV Analysis of Major Birth Defects

2020 ◽  
Vol 21 (21) ◽  
pp. 8247
Author(s):  
Alina Christine Hilger ◽  
Gabriel Clemens Dworschak ◽  
Heiko Martin Reutter
Keyword(s):  
Birth Defects ◽  
Copy Number ◽  
Congenital Malformations ◽  
De Novo ◽  
Copy Number Variations ◽  
Lessons Learned ◽  
Organ System ◽  
Molecular Karyotyping ◽  
The Past ◽  
Single Organ

The treatment of major birth defects are key concerns for child health. Hitherto, for the majority of birth defects, the underlying cause remains unknown, likely to be heterogeneous. The implicated mortality and/or reduced fecundity in major birth defects suggest a significant fraction of mutational de novo events among the affected individuals. With the advent of systematic array-based molecular karyotyping, larger cohorts of affected individuals have been screened over the past decade. This review discusses the identification of disease-causing copy-number variations (CNVs) among individuals with different congenital malformations. It highlights the differences in findings depending on the respective congenital malformation. It looks at the differences in findings of CNV analysis in non-isolated complex congenital malformations, associated with central nervous system malformations or intellectual disabilities, compared to isolated single organ-system malformations. We propose that the more complex an organ system is, and the more genes involved during embryonic development, the more likely it is that mutational de novo events, comprising CNVs, will confer to the expression of birth defects of this organ system.

scholarly journals Chromosomal copy number heterogeneity predicts survival rates across cancers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Erik van Dijk ◽  
Tom van den Bosch ◽  
Kristiaan J. Lenos ◽  
Khalid El Makrini ◽  
Lisanne E. Nijman ◽  
...  
Keyword(s):  
Copy Number ◽  
Cancer Survival ◽  
Survival Rates ◽  
Cancer Prognosis ◽  
Disease Outcomes ◽  
Distinct Disease ◽  
Cancer Types ◽  
Chromosomal Copy Number ◽  
Chromosomal Copy ◽  
Pan Cancer

AbstractSurvival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing. Here, we introduce a scalable measure of chromosomal copy number heterogeneity (CNH) that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data and live cell imaging we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 37 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.

scholarly journals SOG1 transcription factor promotes the onset of endoreduplication under salinity stress in Arabidopsis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kalyan Mahapatra ◽  
Sujit Roy
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Transcription Factor ◽  
Programmed Cell Death ◽  
Salinity Stress ◽  
Crucial Role ◽  
Genome Stability ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Regulators

AbstractAs like in mammalian system, the DNA damage responsive cell cycle checkpoint functions play crucial role for maintenance of genome stability in plants through repairing of damages in DNA and induction of programmed cell death or endoreduplication by extensive regulation of progression of cell cycle. ATM and ATR (ATAXIA-TELANGIECTASIA-MUTATED and -RAD3-RELATED) function as sensor kinases and play key role in the transmission of DNA damage signals to the downstream components of cell cycle regulatory network. The plant-specific NAC domain family transcription factor SOG1 (SUPPRESSOR OF GAMMA RESPONSE 1) plays crucial role in transducing signals from both ATM and ATR in presence of double strand breaks (DSBs) in the genome and found to play crucial role in the regulation of key genes involved in cell cycle progression, DNA damage repair, endoreduplication and programmed cell death. Here we report that Arabidopsis exposed to high salinity shows generation of oxidative stress induced DSBs along with the concomitant induction of endoreduplication, displaying increased cell size and DNA ploidy level without any change in chromosome number. These responses were significantly prominent in SOG1 overexpression line than wild-type Arabidopsis, while sog1 mutant lines showed much compromised induction of endoreduplication under salinity stress. We have found that both ATM-SOG1 and ATR-SOG1 pathways are involved in the salinity mediated induction of endoreduplication. SOG1was found to promote G2-M phase arrest in Arabidopsis under salinity stress by downregulating the expression of the key cell cycle regulators, including CDKB1;1, CDKB2;1, and CYCB1;1, while upregulating the expression of WEE1 kinase, CCS52A and E2Fa, which act as important regulators for induction of endoreduplication. Our results suggest that Arabidopsis undergoes endoreduplicative cycle in response to salinity induced DSBs, showcasing an adaptive response in plants under salinity stress.

Abstract 1918 P122 Protein, a Positive Regulator for Phospholipase C-σ1, Is Upregulated and Involved in Enhanced Calcium Signaling in Human Coronary Spasm

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Reiichi Murakami ◽  
Tomohiro Osanai ◽  
Hirofumi Tomita ◽  
Ken Okumura
Keyword(s):  
Protein Expression ◽  
Phospholipase C ◽  
Protein A ◽  
Coronary Spasm ◽  
Amino Acid Replacement ◽  
Hek293 Cells ◽  
Gene Expressions ◽  
Human Embryonic Kidney Cells ◽  
Control Subjects ◽  
Intracellular Ca

We previously showed that the activity of phospholipase C (PLC)-σ1, a key enzyme for Ca 2+ signaling in the coronary artery smooth muscle, was enhanced threefold in patients with coronary spastic angina (CSA) compared with control subjects. Structural mutation of PLC-σ1 (864G-A) variant with the amino acid replacement of arginine 257 by histidine is one mechanism for the enhanced PLC-σ1 activity, but this was observed in only 10% of CSA patients. PLC-σ1 was shown to be positively regulated by p122 protein. We examined the possible role of p122 protein in the mechanism for enhanced PLC-σ1 activity. In 11 patients with CSA and 9 control subjects without CSA, skin fibroblasts were obtained at the coronary angiography and were cultured. Protein and gene expressions of p122 were determined by Western blot analysis and real-time quantitative RT-PCR, respectively. The protein expression of p122 was enhanced in CSA threefold compared with control subjects (237±17 vs 85±13 units, p<0.0001). The gene expression of p122 was also enhanced in CSA by 36.1±8.7% compared with control (p<0.01). We further examined whether the upregulated p122 protein is associated with the enhancement of intracellular Ca 2+ signaling. Human embryonic kidney cells (HEK293) were cultured and transfected by muscarine M1 receptor. In the cells expressing normal PLC-σ1, acethylcholine (ACh) at 10 −6 and 10 −5 mol/L caused a dose-dependent, rapid transient increase in [Ca 2+ ] i followed by a lower but sustained phase of the increase. We further transfected the HEK293 cells by p122, which resulted in the increased expression of p122 protein two-to threefold. [Ca 2+ ] i at baseline was 23±1 nmol/L in the cells without p122 transfection and 39±2 nmol/L in those with p122 (P<0.01). The peak increase in [Ca 2+ ] i from the baseline after ACh was significantly greater in the cells transfected with p122 than in those without transfection (68±6 versus 33±4 nmol/L at 10 −6 mol/L Ach, and 128±11 versus 67±8 nmol/L at 10 −5 mol/L ACh, both P<0.01). The sustained phase of [Ca 2+ ] i increase was prolonged in the cells with p122 transfection compared with those without transfection. In conclusion, the enhanced p122 protein expression is involved in the pathogenesis of CSA by enhancing intracellular Ca 2+ signaling.

scholarly journals Functions of Cyclin A1 in the Cell Cycle and Its Interactions with Transcription Factor E2F-1 and the Rb Family of Proteins

1999 ◽  
Vol 19 (3) ◽  
pp. 2400-2407 ◽  
Author(s):  
Rong Yang ◽  
Carsten Müller ◽  
Vong Huynh ◽  
Yuen K. Fung ◽  
Amy S. Yee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Mitotic Cell ◽  
Histone H1 ◽  
Mitotic Cell Cycle ◽  
Osteosarcoma Cell ◽  
Cell Cycle Regulators ◽  
Cyclin A1 ◽  
Transcription Factor E2f

ABSTRACT Human cyclin A1, a newly discovered cyclin, is expressed in testis and is thought to function in the meiotic cell cycle. Here, we show that the expression of human cyclin A1 and cyclin A1-associated kinase activities was regulated during the mitotic cell cycle. In the osteosarcoma cell line MG63, cyclin A1 mRNA and protein were present at very low levels in cells at the G0 phase. They increased during the progression of the cell cycle and reached the highest levels in the S and G2/M phases. Furthermore, the cyclin A1-associated histone H1 kinase activity peaked at the G2/M phase. We report that cyclin A1 could bind to important cell cycle regulators: the Rb family of proteins, the transcription factor E2F-1, and the p21 family of proteins. The in vitro interaction of cyclin A1 with E2F-1 was greatly enhanced when cyclin A1 was complexed with CDK2. Associations of cyclin A1 with Rb and E2F-1 were observed in vivo in several cell lines. When cyclin A1 was coexpressed with CDK2 in sf9 insect cells, the CDK2-cyclin A1 complex had kinase activities for histone H1, E2F-1, and the Rb family of proteins. Our results suggest that the Rb family of proteins and E2F-1 may be important targets for phosphorylation by the cyclin A1-associated kinase. Cyclin A1 may function in the mitotic cell cycle in certain cells.

Role of Copy Number Variants in Structural Birth Defects: TABLE 1

PEDIATRICS ◽  
2012 ◽  
Vol 129 (4) ◽  
pp. 755-763 ◽  
Author(s):  
Abigail E. Southard ◽  
Lisa J. Edelmann ◽  
Bruce D. Gelb
Keyword(s):  
Birth Defects ◽  
Copy Number ◽  
Copy Number Variants
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