Project description:The effects of DNASE1L3 or DNASE1 deficiency on cfDNA methylation was explored in plasma of mice deficient in these nucleases and in DNASE1L3-deficient humans. Compared to wildtype cfDNA, cfDNA in Dnase1l3-deficient mice was significantly hypomethylated, while cfDNA in Dnase1-deficient mice was hypermethylated. The cfDNA hypomethylation in Dnase1l3-deficient mice was due to increased fragmentation and representation from open chromatin regions (OCRs) and CpG islands (CGIs). These findings were absent in Dnase1-deficient mice.
Project description:The effects of DNASE1L3 or DNASE1 deficiency on cfDNA methylation was explored in plasma of mice deficient in these nucleases and in DNASE1L3-deficient humans. Compared to wildtype cfDNA, cfDNA in Dnase1l3-deficient mice was significantly hypomethylated, while cfDNA in Dnase1-deficient mice was hypermethylated. The cfDNA hypomethylation in Dnase1l3-deficient mice was due to increased fragmentation and representation from open chromatin regions (OCRs) and CpG islands (CGIs). These findings were absent in Dnase1-deficient mice.
Project description:Expression of key transcription factors Klf4, Oct3/4, Sox2, and c-Myc (KOSM) in embryonic stem cells can reprogram somatic cells into pluripotent cells. We found that two histone variants, TH2A and TH2B, and histone chaperone Npm enhance the KOSM-dependent generation of induced pluripotent cells (iPSCs) and produce iPSCs only with Klf4 and Oct3/4. To identify directly affected genes by these histone variants during reprogramming, we carried out gene expression profiling of MEFs overexpressing TH2A/TH2B/Npm and TH2A/TH2B deficient MEFs after infection with retroviruses expressing KOSM. A total of 21 Affymetrix Mouse Gene ST array were done for mRNA expression profiling of ES cells, iPS cells induced by Klf4, Oct4, Sox2, and c-Myc (KOSM) or Klf4, Oct4, Th2a, Th2b, and p-Npm (KOBAN), wild-type MEFs infected with retrovirus vectors expressing KOSM, KOSMBAN, or empty vector and Th2a/Th2b-deficient MEFs infected with retrovirus vector expressing KOSM.
Project description:The dataset contains sequencing data in wildtype, Dnase1-deficient and Dnase1l3-deficient mice. We performed 2 x 75bp paired-end whole genome bisulfite sequencing of pooled plasma cell-free DNA (cfDNA) and buffy coat genomic DNA. The effects of DNASE1L3 or DNASE1 deficiency on cfDNA methylation was explored in plasma of mice deficient in these nucleases.
Project description:Begitt2014 - STAT1 cooperative DNA binding - single GAS polymer model
The importance of STAT1-cooperative DNA binding in type 1 and type 2 interferon signalling has been studies using experimental and modelling approaches. The authors have developed two ODE models to describe STAT1 binding to short promoter regions of DNA, namely "single GAS polymer model" and "double GAS polymer model" considering binding to single or double GAS sites, respectively. The length of DNA in the single GAS model was three sites and four sites in double GAS model. This model correspond to the "single GAS polymer model".
This model is described in the article:
STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling.
Begitt A, Droescher M, Meyer T, Schmid CD, Baker M, Antunes F, Owen MR, Naumann R, Decker T, Vinkemeier U
Nat Immunol. 2014 Feb;15(2):168-76.
Abstract:
STAT1 is an indispensable component of a heterotrimer (ISGF3) and a STAT1 homodimer (GAF) that function as transcription regulators in type 1 and type 2 interferon signaling, respectively. To investigate the importance of STAT1-cooperative DNA binding, we generated gene-targeted mice expressing cooperativity-deficient STAT1 with alanine substituted for Phe77. Neither ISGF3 nor GAF bound DNA cooperatively in the STAT1F77A mouse strain, but type 1 and type 2 interferon responses were affected differently. Type 2 interferon-mediated transcription and antibacterial immunity essentially disappeared owing to defective promoter recruitment of GAF. In contrast, STAT1 recruitment to ISGF3 binding sites and type 1 interferon-dependent responses, including antiviral protection, remained intact. We conclude that STAT1 cooperativity is essential for its biological activity and underlies the cellular responses to type 2, but not type 1 interferon.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000500
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
Project description:Begitt2014 - STAT1 cooperative DNA binding - double GAS polymer model
The importance of STAT1-cooperative DNA binding in type 1 and type 2 interferon signalling has been studies using experimental and modelling approaches. The authors have developed two ODE models to describe STAT1 binding to short promoter regions of DNA, namely "single GAS polymer model" and "double GAS polymer model" considering binding to single or double GAS sites, respectively. The length of DNA in the single GAS model was three sites and four sites in double GAS model. This model correspond to the "double GAS polymer model".
This model is described in the article:
STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling.
Begitt A, Droescher M, Meyer T, Schmid CD, Baker M, Antunes F, Owen MR, Naumann R, Decker T, Vinkemeier U
Nat Immunol. 2014 Feb;15(2):168-76.
Abstract:
STAT1 is an indispensable component of a heterotrimer (ISGF3) and a STAT1 homodimer (GAF) that function as transcription regulators in type 1 and type 2 interferon signaling, respectively. To investigate the importance of STAT1-cooperative DNA binding, we generated gene-targeted mice expressing cooperativity-deficient STAT1 with alanine substituted for Phe77. Neither ISGF3 nor GAF bound DNA cooperatively in the STAT1F77A mouse strain, but type 1 and type 2 interferon responses were affected differently. Type 2 interferon-mediated transcription and antibacterial immunity essentially disappeared owing to defective promoter recruitment of GAF. In contrast, STAT1 recruitment to ISGF3 binding sites and type 1 interferon-dependent responses, including antiviral protection, remained intact. We conclude that STAT1 cooperativity is essential for its biological activity and underlies the cellular responses to type 2, but not type 1 interferon.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000501
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
Project description:Fanconi Anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population. Examination of FANCD2 binding after UV treatment in 293T cells