Postnatal DNA demethylation and its role in tissue maturation.

Published on May 23, 2018in Nature Communications12.121
· DOI :10.1038/S41467-018-04456-6
Yitzhak Reizel11
Estimated H-index: 11
(HUJI: Hebrew University of Jerusalem),
Ofra Sabag7
Estimated H-index: 7
(HUJI: Hebrew University of Jerusalem)
+ 12 AuthorsHoward Cedar87
Estimated H-index: 87
(HUJI: Hebrew University of Jerusalem)
Development in mammals is accompanied by specific de novo and demethylation events that are thought to stabilize differentiated cell phenotypes. We demonstrate that a large percentage of the tissue-specific methylation pattern is generated postnatally. Demethylation in the liver is observed in thousands of enhancer-like sequences associated with genes that undergo activation during the first few weeks of life. Using. conditional gene ablation strategy we show that the removal of these methyl groups is stable and necessary for assuring proper hepatocyte gene expression and function through its effect on chromatin accessibility. These postnatal changes in methylation come about through exposure to hormone signaling. These results define the molecular rules of 5-methyl-cytosine regulation as an epigenetic mechanism underlying cellular responses to. changing environment.
📖 Papers frequently viewed together
48 Citations
7 Authors (Maja Klug, ..., Michael Rehli)
96 Citations
2 Citations
#1Rinho Kim (UPenn: University of Pennsylvania)H-Index: 3
#2Karyn L. Sheaffer (UPenn: University of Pennsylvania)H-Index: 7
Last. Klaus H. Kaestner (UPenn: University of Pennsylvania)H-Index: 118
view all 5 authors...
: Methylated cytosines are associated with gene silencing. The ten-eleven translocation (TET) hydroxylases, which oxidize methylated cytosines to 5-hydroxymethylcytosine (5hmC), are essential for cytosine demethylation. Gene silencing and activation are critical for intestinal stem cell (ISC) maintenance and differentiation, but the potential role of TET hydroxylases in these processes has not yet been examined. Here, we generated genome-wide maps of the 5hmC mark in ISCs and their differentiate...
35 CitationsSource
#1Matthew V. Cannon (Cleveland Clinic)H-Index: 10
#2Genay Pilarowski (Cleveland Clinic)H-Index: 6
Last. David Serre (Cleveland Clinic)H-Index: 18
view all 4 authors...
DNA methylation is traditionally thought to be established during early development and to remain mostly unchanged thereafter in healthy tissues, although recent studies have shown that this epigenetic mark can be more dynamic. Epigenetic changes occur in the liver after birth, but the timing and underlying biological processes leading to DNA methylation changes are not well understood. We hypothesized that this epigenetic reprogramming was the result of terminal differentiation of hepatocyte pr...
10 CitationsSource
#1Shari Orlanski (HUJI: Hebrew University of Jerusalem)H-Index: 6
#2Verena LabiH-Index: 22
Last. Yehudit Bergman (HUJI: Hebrew University of Jerusalem)H-Index: 40
view all 11 authors...
There is ample evidence that somatic cell differentiation during development is accompanied by extensive DNA demethylation of specific sites that vary between cell types. Although the mechanism of this process has not yet been elucidated, it is likely to involve the conversion of 5mC to 5hmC by Tet enzymes. We show that a Tet2/Tet3 conditional knockout at early stages of B-cell development largely prevents lineage-specific programmed demethylation events. This lack of demethylation affects the e...
55 CitationsSource
#1Kasper D. Rasmussen (UCPH: University of Copenhagen)H-Index: 14
#2Kristian HelinH-Index: 116
The pattern of DNA methylation at cytosine bases in the genome is tightly linked to gene expression, and DNA methylation abnormalities are often observed in diseases. The ten eleven translocation (TET) enzymes oxidize 5-methylcytosines (5mCs) and promote locus-specific reversal of DNA methylation. TET genes, and especially TET2, are frequently mutated in various cancers, but how the TET proteins contribute to prevent the onset and maintenance of these malignancies is largely unknown. Here, we hi...
400 CitationsSource
#1Amanda M. Ackermann (UPenn: University of Pennsylvania)H-Index: 10
#2Zhiping Wang (UPenn: University of Pennsylvania)H-Index: 2
Last. Klaus H. Kaestner (UPenn: University of Pennsylvania)H-Index: 118
view all 5 authors...
Abstract Objective Although glucagon-secreting α-cells and insulin-secreting β-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and exhibit overlapping transcriptomes and epigenomes. Notably, destruction of β-cells can stimulate repopulation via transdifferentiation of α-cells, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both α- and β-cells contributes to the pathophysiology...
125 CitationsSource
#1Aziz Khan (THU: Tsinghua University)H-Index: 10
#2Xuegong Zhang (THU: Tsinghua University)H-Index: 47
Super-enhancers are clusters of transcriptional enhancers that drive cell-type-specific gene expression and are crucial to cell identity. Many disease-associated sequence variations are enriched in super-enhancer regions of disease-relevant cell types. Thus, super-enhancers can be used as potential biomarkers for disease diagnosis and therapeutics. Current studies have identified super-enhancers in more than 100 cell types and demonstrated their functional importance. However, a centralized reso...
216 CitationsSource
#1Silvia Domcke (University of Basel)H-Index: 2
#2Anaïs F. Bardet (FMI: Friedrich Miescher Institute for Biomedical Research)H-Index: 11
Last. Dirk Schübeler (University of Basel)H-Index: 71
view all 6 authors...
The relationship between DNA methylation and transcription factor binding was studied across the genome in mouse embryonic stem cells-the study reveals that the transcription factor NRF1 is methylation-sensitive and how physiological binding of NRF1 relies on local removal of DNA methylation.
257 CitationsSource
#1Dana Avrahami (UPenn: University of Pennsylvania)H-Index: 17
#2Changhong Li (Children's Hospital of Philadelphia)H-Index: 32
Last. Klaus H. Kaestner (UPenn: University of Pennsylvania)H-Index: 118
view all 11 authors...
Aging is driven by changes of the epigenetic state that are only partially understood. We performed a comprehensive epigenomic analysis of the pancreatic β cell, key player in glucose homeostasis, in adolescent and very old mice. We observe a global methylation drift resulting in an overall more leveled methylome in old β cells. Importantly, we discover targeted changes in the methylation status of β cell proliferation and function genes that go against the global methylation drift, are specific...
118 CitationsSource
#1Timothy H. Bestor (Columbia University)H-Index: 73
#2John R. Edwards (WashU: Washington University in St. Louis)H-Index: 27
Last. Mathieu Boulard (Columbia University)H-Index: 9
view all 3 authors...
It has been nearly 40 y since it was suggested that genomic methylation patterns could be transmitted via maintenance methylation during S phase and might play a role in the dynamic regulation of gene expression during development [Holliday R, Pugh JE (1975) Science 187(4173):226–232; Riggs AD (1975) Cytogenet Cell Genet 14(1):9–25]. This revolutionary proposal was justified by “... our almost complete ignorance of the mechanism for the unfolding of the genetic program during development” that p...
127 CitationsSource
#1Camila O. dos Santos (Watson School of Biological Sciences)H-Index: 10
#2Egor Dolzhenko (SC: University of Southern California)H-Index: 18
Last. Gregory J. Hannon (University of Cambridge)H-Index: 169
view all 5 authors...
Pregnancy is the major modulator of mammary gland activity. It induces a tremendous expansion of the mammary epithelium and the generation of alveolar structures for milk production. Anecdotal evidence from multiparous humans indicates that the mammary gland may react less strongly to the first pregnancy than it does to subsequent pregnancies. Here, we verify that the mouse mammary gland responds more robustly to a second pregnancy, indicating that the gland retains a long-term memory of pregnan...
60 CitationsSource
Cited By28
#1Edward Saehong Oh (CAMH: Centre for Addiction and Mental Health)H-Index: 5
#2A. Petronis (Vilnius University)H-Index: 13
Epigenetics has enriched human disease studies by adding new interpretations to disease features that cannot be explained by genetic and environmental factors. However, identifying causal mechanisms of epigenetic origin has been challenging. New opportunities have risen from recent findings in intra-individual and cyclical epigenetic variation, which includes circadian epigenetic oscillations. Cytosine modifications display deterministic temporal rhythms, which may drive ageing and complex disea...
#1Álvaro del Real (UC: University of Cantabria)H-Index: 6
#2Ana Santurtún (UC: University of Cantabria)H-Index: 11
Last. M. Teresa Zarrabeitia (UC: University of Cantabria)H-Index: 2
view all 3 authors...
ABSTRACT The exposure to airborne particulate matter (PM) increases the risk of developing human diseases. Epigenetic mechanisms have been related to environmental exposures and human diseases. The present review is focused on current available studies, which show the relationship between epigenetic marks, exposure to air pollution and human’s health. Air contaminants involved in epigenetic changes have been related to different specific mechanisms (DNA methylation, post-translational histone mo...
#1Yitzhak Reizel (UPenn: University of Pennsylvania)H-Index: 11
#2Ashleigh Morgan (UPenn: University of Pennsylvania)H-Index: 5
Last. Klaus H. Kaestner (UPenn: University of Pennsylvania)H-Index: 118
view all 10 authors...
Summary Tissue-specific DNA methylation patterns are created by transcription factors that recruit methylation and demethylation enzymes to cis-regulatory elements. To date, it is not known whether transcription factors are needed to continuously maintain methylation profiles in development and mature tissues or whether they only establish these marks during organ development. We queried the role of the pioneer factor FoxA in generating hypomethylated DNA at liver enhancers. We discovered a set ...
1 CitationsSource
#1Mahavir Singh (University of Louisville)H-Index: 22
#2Shanna J. Hardin (University of Louisville)H-Index: 2
Last. Suresh C. Tyagi (University of Louisville)H-Index: 82
view all 7 authors...
Although high-fat diet (HFD) induces gut dysbiosis and cardiovascular system remodeling, the precise mechanism is unclear. We hypothesize that HFD instigates dysbiosis and cardiac muscle remodeling by inducing matrix metalloproteinases (MMPs) that lead to an increase in white adipose tissue and treatment with lactobacillus (a ketone body donor from lactate; the substrate for the mitochondria) reverses dysbiosis-induced cardiac injury, in part, by increasing lipolysis (PGC-1α, and UCP1), adipose ...
#1Claudia E. Oropeza (UIC: University of Illinois at Chicago)H-Index: 10
#2Grant Tarnow (UIC: University of Illinois at Chicago)H-Index: 1
Last. Alan McLachlan (UIC: University of Illinois at Chicago)H-Index: 37
view all 8 authors...
HBV transcription and replication increases progressively throughout postnatal liver development with maximal viral biosynthesis occurring at around four weeks of age in the HBV transgenic mouse model of chronic infection. Increasing viral biosynthesis is associated with a corresponding progressive loss of DNA methylation. The loss of DNA methylation is associated with increasing levels of 5-hydroxymethylcytosine (5hmC) residues which correlates with increased liver-enriched pioneer transcriptio...
#1Tatiana L. Fonseca (U of C: University of Chicago)H-Index: 17
#2Tzintzuni Garcia (U of C: University of Chicago)H-Index: 6
Last. Antonio C. Bianco (U of C: University of Chicago)H-Index: 79
view all 5 authors...
In the neonatal liver, a peak of type 2 deiodinase (D2) activity accelerates local T3 production and the expression of thyroid hormone (TH)-responsive genes. Here we show that this acute increase in T3 signaling permanently modifies hepatic gene expression. Liver-specific Dio2 inactivation (Alb-D2KO) transiently increased H3K9me3 levels during post-natal days 1-5 (P1-P5) in discrete chromatin areas, and methylation of 1,508 DNA sites (H-sites) that remained in the adult mouse liver. These sites ...
#1Pengying Hao (BU: Boston University)H-Index: 3
#2David J. Waxman (BU: Boston University)H-Index: 105
Growth hormone-activated STAT5b is an essential regulator of sex-differential gene expression in mouse liver; however, its impact on hepatic gene expression and epigenetic responses is poorly understood. Here, we found a substantial, albeit incomplete loss of liver sex bias in hepatocyte-specific STAT5a/STAT5b (collectively, STAT5)-deficient mouse liver. In male liver, many male-biased genes were downregulated in direct association with the loss of STAT5 binding; many female-biased genes, which ...
#1Yitzhak Reizel (UPenn: University of Pennsylvania)H-Index: 11
#2Ashleigh Morgan (UPenn: University of Pennsylvania)H-Index: 5
Last. Klaus H. Kaestner (UPenn: University of Pennsylvania)H-Index: 118
view all 9 authors...
The FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex regulatory network thought to become progressively resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the dispensability of FoxA factors for maintaining this regulatory network, we ablated all FoxA genes in the adult mouse liver. Remarkably, loss of FoxA caused rapid and massive reduction in the expression of...
7 CitationsSource
#1Asher Ornoy (HUJI: Hebrew University of Jerusalem)H-Index: 75
#2Maria Becker (Ariel University)H-Index: 1
Last. Zivanit Ergaz (HUJI: Hebrew University of Jerusalem)H-Index: 17
view all 4 authors...
S-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss in some length the process of DNA methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. We also discuss the effects of SAMe de...
4 CitationsSource
#1Akash K. George (University of Louisville)H-Index: 11
#2Mahavir Singh (University of Louisville)H-Index: 22
Last. Suresh C. Tyagi (University of Louisville)H-Index: 9
view all 6 authors...
: Unless there is a genetic defect/mutation/deletion in a gene, the causation of a given disease is chronic dysregulation of gut metabolism. Most of the time, if not always, starts within the gut; that is what we eat. Recent research shows that the imbalance between good versus bad microbial population, especially in the gut, causes systemic diseases. Thus, an appropriate balance of the gut microbiota (eubiosis over dysbiosis) needs to be maintained for normal health (Veeranki and Tyagi, 2017, J...
12 CitationsSource