Thursday, October 2, 2014

Cracking the Code

RNA polymerases IV (green) and II (red) in the nucleus of an Arabidopsis
(rockcress) plant cell - Image: Dr. Olga Pontes, University of Indiana
One of evolution's deepest mysteries has been solved. Indiana University researchers have discovered how the effects of experience - environmental circumstances - can be handed down from parents to their offspring - without changes to DNA sequences.

According to IU biochemist Dr. Craig Pikaard, the secret to such epigenetic ("above the genes") inheritance lies in gene silencing patterns which can be preserved and passed down through generations. Instead of relying upon information hardwired by the DNA sequence, parent cells use chemical tags as guides for switching off the protein-manufacturing capability of specific DNA regions known as genes.

In essence, cells are essentially little more than tiny sacs of chemical reactions, all run by thousands of special proteins called enzymes, which float about the cytoplasm within your cells, conducting all the work these cells require. These molecules are tiny chemical-reaction machines, enabling your cells to conduct rapid chemical reactions every moment of your life, assembling and disassembling molecules when necessary, allowing cell growth and reproduction, among other functions.

In 1999, Dr. Pikaard discovered two gene-silencing plant enzymes: Pol IV and Pol V. These are RNA polymerases,  so-named because they are enzymes (denoted by the -ase suffix) used to create polymers (long chain molecules) of RNA molecules, the universal chemical blueprints which guide the assembly of proteins, the building blocks of life.

Dr. Pikaard's newest findings show how these enzymes shape plant development.

Genes aren't automatically silenced during normal DNA replication, but chemical markers can be added, providing a molecular memory which allows an offspring's cells to recognize which genes should be silenced. This allows modifications to be passed down without altering an organism's natural DNA sequence, just as installing a new program can alter a computer's functions without a change in its components.

Single-carbon (methyl) or double-carbon (acetyl) chemical tags can be added to or removed from DNA strands (chromatin), providing epigenetic information to the DNA sequence, which in turn guides RNA-assembly.

Short-interfering RNAs (siRNA) are tiny RNA molecules which guide methyl group attachment to DNA strands, deactivating specific gene sequences - the process called RNA-directed DNA methylation (RdDM).

This inheritance, called silent locus identity is controlled by two enzymes which work in tandem to control the chemical tagging responsible for epigenetic memory: histone deacetylase 6 (HDA6) which removes acetyl groups from histones (the protein spools around which chromatic strands wrap), and methyltransferase (MET1), used for DNA maintenance.

HDA6 and MET1 control the recruitment of Pol IV, the synthesis of siRNA and finally the process of RdDM, the final step in this form of gene silencing. The effects can be dramatic - sporadically-occurring diseases like cancer often seem to arise from such epigenetic changes to DNA.

Source: "Gene silencing instructions acquired through 'molecular memory' tags on chromatin - New work identifies machinery of epigenetic inheritance, relevant to development and cancer", press release, Stephen Chaplin, March 20, 2014, Indiana University

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