Chromatin Basics

Introduction

Chromatin is DNA bound to histones and quite a number of other associated factors including countless transcription factors. Naked DNA with no bound proteins is kind of like plain spaghetti, when you add the sauce, the spaghetti takes on a whole new character that depends on the nature of the sauce and its ingredients. In this analogy, the histones are kind of like meatballs that come in groups of eight (octamers) that can each have different flavors depending on their modifications and associated proteins. Taken together the relative chromatin state of a particular DNA region has many functional consequences including on gene transcription and more broadly on cell biology.

Histones

Histones H1, H2A, H2B, H3, and H4 all play key roles in chromatin structure. While H1 is a linker histone, the other 4 histone proteins are present in two copies each comprising an octamer around which DNA winds forming a nucleosome. A great deal of complexity of chromatin comes from the fact that histones can be post-translationally modified in many ways including phosphorylation, methylation, acetylation, sumoylation, ubiquitination, and more. Adding to the complexity of this code is the fact that these modifications can occur at multiple lysine residues in a huge number of potential combinations within each nucleosome. The current model in the field is that together the histone modifications code for the activity state of the chromatin in which they reside. In addition, histone variants play central roles in chromatin structure and function. Yet another layer of the code is given by the methylation status of the DNA itself with methylated CpG being associated with more inactive chromatin.

Chromatin modifying enzymes

The modifications of the histones and DNA itself are mediated by a large and growing list of enzymes. Often the level of a specific modification is dictated by the balance of two antagonistic enzymes: one that mediates the modification and one that reverses it. In this way cells maintain the required balance of chromatin modifications. For example, lysines can be acetylated by histone acetyl transferases or "HATs" while the same lysines can be deacetylated by histone deacetylases or "HDACs". It is not entirely clear which HATs and which HDACs are responsible for directing the acetylation of specific lysines in specific histones. There appears to be some degree of promiscuity in this system. Similarly while specific histone methyl transferases (KMT)are known to methylate specific lysine residues, demethylases (KDM) have been found to remove methyl groups.

Chromatin Function

Chromatin controls the manner in which the information stored in DNA in turn influences essentially all aspects of cell behavior through impacting RNA transcription of individual protein coding genes, rRNAs, lncRNAs, and miRNA. Chromatin also directs normal embryonic development and regulates stem cell behavior. It also impacts the cell cycle including chromatin condensation during mitosis and DNA replication during S phase. Aberrant chromatin states appear to play a key role in many diseases including developmental disorders and most if not all tumors, including an area of focus in our lab, childhood brain tumors.