DNA methylation and imprinting: why bother?

doi:10.1016/S0168-9525(97)01180-3

Trends in Genetics

Volume 13, Issue 8, August 1997, Pages 323-329

https://doi.org/10.1016/S0168-9525(97)01180-3 Get rights and content

Abstract

DNA methylation is crucial for mammalian development because embryos that cannot maintain normal methylation levels die after gastrulation. I propose that DNA methylation is only important for the somatic lineages, but has no role in embryonic lineages including the germ line. Among vertebrates, genomic imprinting is found only in mammals, and numerous hypothesis have ascribed an essential function to imprinting because of the uniquely mammalian developmental and physiological requirements. However, our understanding of molecular details of the imprinting process, as well as evolutionary considerations, is rather consistent with imprinting having no intrinsic role in mammalian development.

References (68)

A. Efstratiadis
Curr. Biol.
(1994)
J. Sanford et al.
Trends Genet.
(1985)
P. Soriano et al.
Cell
(1986)
F. Antequera et al.
Cell
(1990)
T.H. Bestor et al.
J. Mol. Biol.
(1988)
A. Weiss et al.
Cell
(1996)
E. Li et al.
Cell
(1992)
R. Stoger
Cell
(1993)
T. Ludwig
Dev. Biol.
(1996)
D.P. Norris
Cell
(1994)

D. Patterton et al.

Dev. Biol.

(1996)

T. Moore et al.

Trends Genet.

(1991)

P. Zhang

Nature

(1997)

S. Varmuza et al.

Trends Genet.

(1994)

T. DeChiara et al.

Cell

(1991)

E.E. Keverne

Dev. Brain Res.

(1996)

A. Bird

Trends Genet.

(1995)

J. McGrath et al.

Nature

(1984)

B.M. Cattanach et al.

Nature

(1985)

D.P. Barlow

Science

(1995)

R.H. Fundele et al.

Dev. Genet.

(1994)

P.A. Leighton et al.

Biol. Reprod.

(1996)

W. Reik

Trends Genet.

(1989)

J.D. Brenton et al.

Cancer Surv.

(1995)

M. Monk et al.

Development

(1987)

T. Kafri

Genes Dev.

(1992)

A. Razin et al.

Hum. Mol. Genet.

(1995)

D. Jähner

Nature

(1982)

C. Stewart et al.

P. Laird et al.

Annu. Rev. Genet.

(1996)

T. Bestor

EMBO J.

(1992)

H. Lei

Development

(1996)

B. Panning et al.

Genes Dev.

(1996)

E. Li et al.

Nature

(1993)

Cited by (327)

AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of hematopoietic stem cells
2023, Cell Reports Methods
Small molecules have enabled expansion of hematopoietic stem and progenitor cells (HSPCs), but limited knowledge is available on whether these agonists can act synergistically. In this work, we identify a stem cell agonist in AA2P and optimize a series of stem cell agonist cocktails (SCACs) to help promote robust expansion of human HSPCs. We find that SCACs provide strong growth-promoting activities while promoting retention and function of immature HSPC. We show that AA2P-mediated HSPC expansion is driven through DNA demethylation leading to enhanced expression of AXL and GAS6. Further, we demonstrate that GAS6 enhances the serial engraftment activity of HSPCs and show that the GAS6/AXL pathway is critical for robust HSPC expansion.
HD-Zip IV transcription factors: Drivers of epidermal cell fate integrate metabolic signals
2023, Current Opinion in Plant Biology
The leaf epidermis comprises the outermost layer of cells that protect plants against environmental stresses such as drought, ultraviolet radiation, and pathogen attack. Research over the past decades highlights the role of class IV homeodomain leucine-zipper (HD-Zip IV) transcription factors (TFs) in driving differentiation of various epidermal cell types, such as trichomes, guard cells, and pavement cells. Evolutionary origins of this family in the charophycean green algae and HD-Zip-specific gene expression in the maternal genome provide clues to unlocking their secrets which include ties to cell cycle regulation. A distinguishing feature of these TFs is the presence of a lipid binding pocket that integrates metabolic information with gene expression. Identities of metabolic partners are beginning to emerge, uncovering feedback loops to maintain epidermal cell specification. Discoveries of associated molecular mechanisms are revealing fascinating links to phospholipid and sphingolipid metabolism and mechanical signaling.
Cancer plasticity: Investigating the causes for this agility
2023, Seminars in Cancer Biology
Citation Excerpt :
The methylation of CpG islands results in the downregulation of gene expression (Fig. 4B). DNA methylation is an important process in early development, during which the methylation pattern is erased, and a unique DNA methylation pattern is created that helps in regulating tissue-specific expression [71]. The same mechanism is exploited during cancer plasticity where cancer cells often deregulate methylation thereby impacting gene expression [72,76].
Cancer is not a hard-wired phenomenon but an evolutionary disease. From the onset of carcinogenesis, cancer cells continuously adapt and evolve to satiate their ever-growing proliferation demands. This results in the formation of multiple subtypes of cancer cells with different phenotypes, cellular compositions, and consequently displaying varying degrees of tumorigenic identity and function. This phenomenon is referred to as cancer plasticity, during which the cancer cells exist in a plethora of cellular states having distinct phenotypes. With the advent of modern technologies equipped with enhanced resolution and depth, for example, single-cell RNA-sequencing and advanced computational tools, unbiased cancer profiling at a single-cell resolution are leading the way in understanding cancer cell rewiring both spatially and temporally. In this review, the processes and mechanisms that give rise to cancer plasticity include both intrinsic genetic factors such as epigenetic changes, differential expression due to changes in DNA, RNA, or protein content within the cancer cell, as well as extrinsic environmental factors such as tissue perfusion, extracellular milieu are detailed and their influence on key cancer plasticity hallmarks such as epithelial-mesenchymal transition (EMT) and cancer cell stemness (CSCs) are discussed. Due to therapy evasion and drug resistance, tumor heterogeneity caused by cancer plasticity has major therapeutic ramifications. Hence, it is crucial to comprehend all the cellular and molecular mechanisms that control cellular plasticity. How this process evades therapy, and the therapeutic avenue of targeting cancer plasticity must be diligently investigated.
DNA methylation: a historical perspective
2022, Trends in Genetics
Citation Excerpt :
A quarter century ago, one of the pioneers in the field of DNA methylation, Rudolf Jaenisch, outlined in the August 1997 issue of Trends in Genetics why we should bother caring about DNA methylation and speculated in which developmental contexts it might function [1].
In 1925, 5-methylcytosine was first reported in bacteria. However, its biological importance was not intuitive for several decades. After this initial lag, the ubiquitous presence of this methylated base emerged across all domains of life and revealed a range of essential biological functions. Today, we are armed with the knowledge of the key factors that establish, maintain, and remove DNA methylation and have access to a staggering and rapidly growing number of base-resolution methylation maps. Despite this, several fundamental details about the precise role and interpretation of DNA methylation patterns remain under investigation. Here, we review the field of DNA methylation from its beginning to present day, with an emphasis on findings in mammalian systems, and point the reader to select experiments that form the foundation of this field.
A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers
2018, Cell Reports
Cancer progression to an aggressive phenotype often co-opts aspects of stem cell biology. Here, we developed gene signatures for normal human stem cell populations to understand the relationship between epithelial cancers and stem cell transcriptional programs. Using a pan-cancer approach, we reveal that aggressive epithelial cancers are enriched for a transcriptional signature shared by epithelial adult stem cells. The adult stem cell signature selected for epithelial cancers with worse overall survival and alterations of oncogenic drivers. Lethal small cell neuroendocrine lung, prostate, and bladder cancers transcriptionally converged onto the adult stem cell signature and not other stem cell signatures tested. We found that DNA methyltransferase expression correlated with adult stem cell signature status and was enriched in small cell neuroendocrine cancers. DNA methylation analysis uncovered a shared epigenomic profile between small cell neuroendocrine cancers. These pan-cancer findings establish a molecular link between human adult stem cells and aggressive epithelial cancers.
Sperm epigenetics and influence of environmental factors
2018, Molecular Metabolism
Developmental programming of the embryo is controlled by genetic information but also dictated by epigenetic information contained in spermatozoa. Lifestyle and environmental factors not only influence health in one individual but can also affect the phenotype of the following generations. This is mediated via epigenetic inheritance i.e., gametic transmission of environmentally-driven epigenetic information to the offspring. Evidence is accumulating that preconceptional exposure to certain lifestyle and environmental factors, such as diet, physical activity, and smoking, affects the phenotype of the next generation through remodeling of the epigenetic blueprint of spermatozoa.
This review will summarize current knowledge about the different epigenetic signals in sperm that are responsive to environmental and lifestyle factors and are capable of affecting embryonic development and the phenotype of the offspring later in life.
Like somatic cells, the epigenome of spermatozoa has proven to be dynamically reactive to a wide variety of environmental and lifestyle stressors. The functional consequence on embryogenesis and phenotype of the next generation remains largely unknown. However, strong evidence of environmentally-driven sperm-borne epigenetic factors, which are capable of altering the phenotype of the next generation, is emerging on a large scale.

View all citing articles on Scopus

View full text

Trends in Genetics

ReviewDNA methylation and imprinting: why bother?

Abstract

Curr. Biol.

Trends Genet.

Cell

Cell

J. Mol. Biol.

Cell

Cell

Cell

Dev. Biol.

Cell

Dev. Biol.

Trends Genet.

Nature

Trends Genet.

Cell

Dev. Brain Res.

Trends Genet.

Nature

Nature

Science

Dev. Genet.

Biol. Reprod.

Trends Genet.

Cancer Surv.

Development

Genes Dev.

Hum. Mol. Genet.

Nature

Annu. Rev. Genet.

EMBO J.

Development

Genes Dev.

Nature

Review
DNA methylation and imprinting: why bother?