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Mapping the marvelous complexity required to build a working human from just 20,000 genes.

The Epigenome Project

Introduction

Man is more than his genes - or is he?

Epigentic modifications

The era of the epigenome


Introduction

"Life is a level of complexity that almost lies outside our vision; it is so far beyond anything we have any means of understanding that we just think of it as a different class of object, a different class of matter" – Douglas Adams The Salmon of Doubt: Hitchhiking the Galaxy One Last Time. 2002

The publication of the first draft of the human genome sequence in 2001 ushered in a new era, building a better understanding of how life functions at a molecular and genetic level. Perhaps most compelling is that this ambitious initiative shed light on a fallacious but widespread understanding in the life sciences. In short, the publication of the human genome brought with it the realization that the information provided solely by nucleotide sequence is surprisingly limited.


Man is more than his genes - or is he?

Prior to completion of the human genome project, the roughly 3 billion bases that compose the human genome was expected to code for a cacophony of genes, as many as 2 million; more “conservative estimates” placed the figure as low as 100,000. Over the course of the human genome project the figure was repeatedly revised and pared down, and at the conclusion the actual number of coding elements was revealed to be stunningly smaller than anyone’s prediction. The figure was initially placed at between 25,000 and 30,000 fundamental units of inheritance, a 2007 further revised the figure around 20,500 and more recently even to a number of less than 20,000 genes. To put this number into perspective, the complete genome for the humble soil nematode Caenorhabditis elegans also codes for about 20,000 genes.

The frugality of the human genome contrasts with the profound complexity and diversity of the human species, and poses a number of interesting questions. Namely, how do you build such a stunningly complex system with so few distinguishable, functional units? A likely piece of the greater answer to this question is found in epigenetics. Epigenetics is the study of heritable cellular, and physiological traits by factors other than DNA sequence.

Epigenetics:

  • Derived from the Greek prefix "epi", meaning over.
  • Involves an additional layer of information coded "on top of" the nucleotide sequence.
  • Is driven in part by simple chemical modifications, like methylation and acetylation to DNA and interacting partners. These changes do not directly change the nucleotide sequence.
  • Plays a role in controlling how, where, and when certain genes are expressed.
  • Much like genetic information, epigenetic changes are heritable through a phenomenon known as "imprinting". However, unlike the relatively stable genome, the epigenome is highly dynamic and heavily influenced by environmental factors.


    Different types of epigenetic changes mediate genetic expression

    Epigenetic changes to DNA like CpG methylation alter three-dimensional conformation of genetic material. These changes may modify how a nucleic acid sequence interacts with various protein partners, like transcription factors - increasing or decreasing the affinity of various transcription factors for the sequence and changing the pattern of gene expression.

    Chemical modifications to DNA-interacting histone-proteins also play a large role in epgienetic regulation. Changes like methylation and acetylation of specific amino acids in histone proteins can impact affinity for DNA, altering how tightly a nucleotide region is wound around a histone. Tightly condensed heterochromatin is inaccessible to transcription machinery, and genes within these regions will be silenced.

    Chromatin Immunprecipitation (ChIP):

    Chromatin immunoprecipitation (ChIP) is the most widely used technique for studying interaction between DNA and interacting proteins like histones and transcription factors.

    ChIP is one of the most powerful tools available to the epigenetics researcher, allowing a researcher to identify and characterize interaction between DNA binding proteins and specific sequences.

    In a ChIP experiment:

  • Antibodies against a protein of interest are used to precipitate a protein/DNA complex from solution.
  • DNA is uncoupled from the associated protein and sequenced, allowing a researcher to characterize sequences that interact with the specific protein of interest.
  • ChIP is a highly sensitive method, and generally requires a very specific antibody with a very high affinity to its target. Antibodies-online currently offers more than 700 verified including antibodies specific for important epigenetic modifiations like histone acetylation and methylation.

    Finally, gene expression can be altered though RNA interference. In RNA interference short antisense RNA sequences silence gene expression by binding DNA and preventing transcription through steric interference, triggering histone or DNA modifications that block transcription, or prompting a process that results in the destruction of transcript mRNA.


    The era of the epigenome

    Epigenetic modifications are heritable changes to a trait or set of traits that are driven by alterations, not to the direct composition of the genetic code, but to a more subtle chemical syntax above the sequence level. Through slight chemical changes to DNA and its interacting partners the expression pattern of genes can be significantly altered. These changes have broad, quantifiable phenotypic impacts on development, manipulating the signals that drive key events like morphogenesis and differentiation. There is a clear and prescient implication of benefits to both basic science and human health research that stems from a more complete understanding of the epigenome. These benefits have driven researchers to flock this field, and funding organizations have followed suit.

    Recently, the NIH Roadmap Epigenomics Project shed even more light on the crucial influence of the epigenome on the transcriptional potential of a variety of cell types. A collection of 21 articles published in nature on 18 February 2015 summarizes the human epigenome for 111 human cell types. The consortium describe histone modification patterns, DNA accessibility, DNA methylation, and RNA expression. They also show that disease- and trait-associated genetic variants are enriched in conjunction with certain tissue-specific epigenomic markers, providing a new resource for interpreting the molecular basis of human disease.

    These results, in conjunction with the results obtained from the ENCODE Consortium in 2012 make it clear that a new era of epigenetics study is now possible, thanks to modern high-throughput techniques like Meth-Seq or ChIP-seq. These new techniques are dependent upon high quality, proven reagents, suggesting that "classical" proteomics research reagents like antibodies are still as relevant and necessary in this field today as they have ever been. (e.g. The ENCODE site alone lists 295 antibodies that are being used in the involved laboratories.)

    Note: antibodies-online offers thousands of products for researching targets of epigenetic relevance, including over 1,800 products from Active Motif an industry leader in production of proteomics tools for investigating epigenetic events like DNA methylation and histone modification.

    Check out all of the Active Motif products, or speak with a technical support scientist today!