The Center for Epigenetics and Metabolism (CEM) at UC Irvine School of Medicine provides a physical, intellectual and organizational environment for the study of epigenetics and its relationship with cellular metabolism. The center fosters collaboration among UC Irvine researchers interested in epigenetics, chromatin remodeling and cellular metabolism.
What is epigenetics?
“Memory” lies at the heart of cellular identity, underscoring the existence of fundamental mechanisms to ensure that cells remember who they are and how they move along elaborate pathways of cellular differentiation, a cornerstone of multicellular organisms.
During development, germ cells or totipotent stem cells give rise to a diverse array of specialized cell types. Cells can be dramatically affected by:
This calls into place a poorly understood “reprogramming process” that may be able to erase previously established settings and, possibly, dedifferentiate or revert these cells to a more primitive pluripotent state.
Thus, it is reasonable to note that the developmental process requires “forward” differentiation with a built-in memory component as well as a “reversible” reprogramming capability, allowing for plasticity.
How could one relatively fixed genome permit this level of flexibility? There must be a system that allows a constant genetic blueprint to be organized in such a way as to accommodate variability resulting from extrinsic and intrinsic signals that come from environmental, dietary and other influences.
Cellular “memory” lies also at the heart of human pathologies, causing us to wonder whether there is a common denominator, or a common set of molecular mechanisms, which once altered result in complex disorders.
For example, how is it that certain lymphocytes “remember” to produce antibodies long after an initial immune threat is over, or that a drug addict “remembers” a long-removed drug high?
In either case, it is yet to be understood what is actually being remembered and how are memories — molecular, cellular or organismal — shaped by past experiences and constant environmental influences. Does a “sculpturing” process exist during development and adult life that takes adaptive cues from the environment or is this molding process purely stochastic in nature, with selection doing the rest?
Are changes in phenotypic responses limited to DNA-based mutations that we inherit from our parents, or can these be adjusted using “epimutations” that could modulate the vast cellular landscapes encountered in multicellular development? What else permits more variability beyond the Watson-Crick DNA double helix?
The epigenetic landscape
A wealth of recent work from many laboratories has rekindled an interest in an old word — epigenetics. It is fitting that epigenetics, as well as the general concept of an “epigenetic landscape,” was first articulated by a developmental biologist, Conrad Waddington, who used the word to explain how identical genotypes could unfold a wide collection of phenotypes as development proceeded.
With time, Waddington’s concept of a phenotypic landscape took on additional meaning — “potentially heritable changes in gene expression that do not involve changes in DNA sequence.”
In today’s biology, epigenetics occupies a central position, jump-started by the sequencing of the human genome and reinforced with clear links to human biology and disease, notably cancer.
Waddington’s landscape has taken a clearer form with the documentation of a remarkable variety of molecular pathways responsible for epigenetic control in all cells. These include multi-subunit complexes that act to remodel chromatin — to exchange specific histones (histone variants) in and out of assembled chromatin — or to enzymatically modify DNA and histone proteins to bring about downstream events.
It is not clear how these dedicated machines are directed to or guided to their target sequences, but it is likely to involve constellations of cis-acting regulatory proteins and non-coding RNAs that engage the DNA template directly.
Some epigenetic marks, such as DNA methylation, appear to provide more stable, if not permanent, indexing marks that extend over long chromosomal domains, giving rise to “memorized” states of gene expression that may be inherited from one cell generation to the next. Thus, epigenetics, defined as the inheritance of non-Mendelian phenotypic alterations, can give rise to heritable alterations in states of gene expression that are not linked to changes in DNA sequence.
Epigenetics and metabolism
Epigenetic control may be exerted through a variety of mechanisms, including:
The interplay of these regulatory mechanisms suggests that the coordinate and progressive combination of these processes may allow the epigenome to move from an “unlocked” to a “locked” state, thereby determining the fate and physiology of a given cell.
Histone PTMs are responsible in large part for the plasticity of chromatin remodeling. Histone modifications are highly dynamic and often reversible events that allow cells to modify their gene transcription, depending on environmental changes.
These events require recruitment of nuclear remodeling factors, often organized in large protein complexes, to induce chromatin transitions and permit or inhibit the access to DNA by transcription factors. Enzymes that modify histone tails, sometimes contained in these complexes as subunits, are brought to a specific region of DNA by DNA-binding proteins and they can either facilitate the access to the DNA or cause further compaction, depending on the tail modification.
Histones are modified at multiple amino acid residues in more than 30 sites within their N-terminal tails. Many different post-translational modifications (acetylation, methylation, phosphorylation, sumoylation, ubiquitination, ADP-ribosylation and biotinylation) can occur, each elicited by specific chromatin remodeling enzymes.
An important consideration relates to the intracellular pathways involved in the marking of these PTMs. Importantly, all of them use metabolites, thereby indicating that the dynamic process of chromatin remodeling “senses” cellular metabolism and changes in energy levels, which are highly controlled and functionally essential in all physiological responses.
One example in which chromatin remodeling directly influences mammalian physiology is the circadian clock, through which at least 15 percent of the genome is controlled. Circadian rhythms govern a wide variety of metabolic functions in most organisms. At the heart of these regulatory pathways is the clock machinery, a remarkably coordinated transcription-translation system that utilizes dynamic changes in chromatin states. We have found that the circadian regulator CLOCK is a histone acetyltransferase (HAT). This characteristic allows CLOCK to relate to a number of other cellular functions and pathologies.
The clock and metabolism
Importantly, the histone deacetylase (HDAC) that counterbalances CLOCK’s enzymatic activity is SIRT1, an enzyme that has been shown to regulate aging, inflammation and metabolism. Strikingly, SIRT1 activity is NAD +- dependent, directly linking cellular energy to epigenetics. Additional recent findings indicate that regulation also goes the other way, since specific elements of the clock are able to sense changes in the cellular metabolism. Intriguing hints and preliminary data indicate that this is only the tip of the iceberg, and that many other pathways of this type operate in the cell.
Understanding in full detail the intimate links between cellular metabolism and epigenetics will provide not only critical insights into system physiology, but also novel avenues toward the pharmacological intervention of metabolic disorders.