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P53 pulses lead to distinct patterns of gene expression albeit similar DNA-binding dynamics.

ABSTRACT: The dynamics of transcription factors play important roles in a variety of biological systems. However, the mechanisms by which these dynamics are decoded into different transcriptional responses are not well understood. Here we focus on the dynamics of the tumor-suppressor protein p53, which exhibits a series of pulses in response to DNA damage. We performed time course RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) measurements to determine how p53 oscillations are linked with gene expression genome wide. We discovered multiple distinct patterns of gene expression in response to p53 pulses. Surprisingly, p53-binding dynamics were uniform across all genomic loci, even for genes that exhibited distinct mRNA dynamics. Using a mathematical model, supported by additional experimental measurements in response to sustained p53 input, we determined that p53 binds to and activates transcription of its target genes uniformly, whereas post-transcriptional mechanisms are responsible for the differences in gene expression dynamics.

SUBMITTER: Hafner A

PROVIDER: S-EPMC5629117 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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p53 pulses lead to distinct patterns of gene expression albeit similar DNA-binding dynamics.

Hafner Antonina A Stewart-Ornstein Jacob J Purvis Jeremy E JE Forrester William C WC Bulyk Martha L ML Lahav Galit G

Nature structural & molecular biology 20170821 10

The dynamics of transcription factors play important roles in a variety of biological systems. However, the mechanisms by which these dynamics are decoded into different transcriptional responses are not well understood. Here we focus on the dynamics of the tumor-suppressor protein p53, which exhibits a series of pulses in response to DNA damage. We performed time course RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) measurements to determine how p53 oscillation ...[more]

PMID: 28825732

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Project description:Pseudohypoparathyroidism type 1A (PHP1A), pseudoPHP (PPHP), and PHP type 1B (PHP1B) are caused by maternal and paternal GNAS mutations and abnormal methylation at maternal GNAS promoter(s), respectively. Adult PHP1A patients are reportedly obese and short, whereas most PPHP patients are born small. In addition to parathyroid hormone (PTH) resistance, PHP1A and PHP1B patients may display early-onset obesity. Because early-onset and severe obesity and short stature are daily burdens for PHP1A patients, we aimed at improving knowledge on the contribution of the GNAS transcripts to fetal and postnatal growth and fat storage. Through an international collaboration, we collected growth and weight data from birth until adulthood for 306 PHP1A/PPHP and 220 PHP1B patients. PHP1A/PPHP patients were smaller at birth than healthy controls, especially PPHP (length Z-score: PHP1A -1.1?±?1.8; PPHP -3.0?±?1.5). Short stature is observed in 64% and 59% of adult PHP1A and PPHP patients. PHP1B patients displayed early postnatal overgrowth (height Z-score at 1 year: 2.2?±?1.3 and 1.3?±?1.5 in autosomal dominant and sporadic PHP1B) followed by a gradual decrease in growth velocity resulting in normal adult height (Z-score for both: -0.4?±?1.1). Early-onset obesity characterizes GNAS alterations and is associated with significant overweight and obesity in adults (bodey mass index [BMI] Z-score: 1.4?±?2.6, 2.1?±?2.0, and 1.4?±?1.9 in PPHP, PHP1A, and PHP1B, respectively), indicating that reduced Gs? expression is a contributing factor. The growth impairment in PHP1A/PPHP may be due to Gs? haploinsufficiency in the growth plates; the paternal XL?s transcript likely contributes to prenatal growth; for all disease variants, a reduced pubertal growth spurt may be due to accelerated growth plate closure. Consequently, early diagnosis and close follow-up is needed in patients with GNAS defects to screen and intervene in case of early-onset obesity and decreased growth velocity. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

Dataset Information

P53 pulses lead to distinct patterns of gene expression albeit similar DNA-binding dynamics.

Publications

p53 pulses lead to distinct patterns of gene expression albeit similar DNA-binding dynamics.

Similar Datasets

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