Dividing cells bookmark their genes

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(Cell, Aug 2012) New research unveils how cells maintain identity through mitosis, when most genes turn off and transcription factors abandon their target sites in DNA.

Every dividing cell faces a series of challenges beyond the basic requirements of making sure that its DNA is fully and faithfully replicated and that its cellular components are properly divvied up. Lately, scientists have typically been more preoccupied with understanding how progenitor cells lay the ground for proper differentiation of their progeny. But there is a flip side of this coin that remains an often underappreciated challenge for : to remain the same.

The identity of cells is dictated by their gene expression profiles, which is in turn controlled by a barrage of protein factors that interact with DNA and direct to a subset of genes to be expressed. However, RNA polymerases and most of these factors separate from DNA during mitosis, something that researchers have always seen as a threat to the identity of dividing cells. Of course, daughter cells can inherit a ready-to-use collection of   and a series of marks that guide those factors to specific places in DNA. That alone could explain to some extent how cells rapidly recreate a specific gene expression landscape after dividing. But scientists have also recently discovered factors that remain associated to when cells divide. In a recent Cell article, Stephan Kadauke and a group of colleagues led by Gerd Blobel at the Childrens Hospital in Philadelphia reported that such binding is critical for the rapid re-expression of key identity genes following mitosis (1).

Using a series of clever tricks, Kadauke and colleagues compared resting vs. mitotic cells with regards to the DNA binding profile of Gata1, a transcription factor required for establishing and maintaining identity. They observed that a very small fraction of sites occupied by Gata1 in non-dividing cells (5.3%) remained bound to Gata1 through mitosis. More importantly, these sites were mostly associated to genes essential for identity, in contrast to other Gata1 targets that have nothing to do with erythro-megakaryocytic differentiation and were not bound by Gata1 in mitotic cells.

The researchers then compared the expression of a selected subset of genes prior and shortly after mitosis. Genes bound by Gata1 through mitosis reached maximum expression following mitosis much more quickly than counterparts that release Gata1 during cell division. Moreover, when Kadauke and colleagues replaced the endogenous Gata1 protein with an engineered construct that ensures the quick degradation of Gata1 during mitosis, they observed that the rapid re-expression of genes “bookmarked” by Gata1 was abrogated.

A burning question remains as to why specific genes ought to be bookmarked through mitosis. Kadauke and colleagues did not report on what happened to the identity of cells in which Gata1 is rapidly degraded during mitosis. Interestingly, some of the targets bookmarked by Gata1 are in fact by this factor, which invites the exciting possibility that a quick re-repression of genes that may confuse a daughter cell’s identity places as much pressure to select for gene bookmarking as ensuring the rapid re-expression of genes that determine a cell’s identity.

Blobel’s team could not yet identify what distinguishes the sites bound by Gata1 during mitosis from the sites that are not. This was not for a lack of trying; they searched for , differential co-binding of Gata1 , differences in and even tried identifying novel sequences that might distinguish both types of sites. But none of the above seemed to explain why Gata1 would bookmark certain sites over others.

Identifying the mechanisms that make transcription factors remain bound to specific targets, and how these aid in maintaining (or otherwise altering) the identity of daughter cells will surely remain an exciting field for a while. Like a bookmark in a book that we can’t wait to go back and read again.

(1) Kadauke S et al. Tissue-specific mitotic bookmarking by hematopoietic transcription factor GATA1. Cell, 2012 Aug 17;150(4):725-37. doi: 10.1016/j.cell.2012.06.038.

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The process by which cells divide is called mitosis. Mitotic cells is a technical way of saying dividing  cells.
RNA polymerases are the proteins inside the nucleus of a cell that can read the sequence of DNA and transcribe it into an RNA molecule, or ‘transcript’. Genetic information is stored in DNA, but cells use RNA transcripts of several kinds to put that information to work.
Transcription factors (TFs) are proteins that recognize and bind specific sequences in DNA to recruit or modulate the activity of the nuclear machinery in charge of expressing genes. Thus, TFs can turn the expression of a gene on or off, or modulate its expression levels.
DNA is wrapped around a very important family of proteins called ‘histones’. Chromatin is the name of the complex of DNA wrapped around histones that is always present in the nucleus of a cell. The concept of chromatin is important because much of the information that a cell needs to know about when, where and how much of a gene to express is encoded as modifications of the histone proteins.
Erythroblasts are the precursor cells that give rise to  erythrocytes, or red blood cells. Normally, erythroblasts proliferate before they terminally commit to becoming an erythrocyte.
Erythrocytes, or red blood cells, are closely related to platelets or ‘thrombocytes’, the blood cells in charge of making blood clots. The precursors of thrombocytes are called megakaryocytes (which means cells with huge nuclei). In fact, erythroblasts and megakaryocytes differentiate from the same progenitor, and that’s why scientists talk about the ‘erythro-megakaryocytic lineage’.
Transcription factors bind to specific DNA sequences in the vicinity of genes and affect their expression. It is not uncommon for the same factor to activate the expression of some genes and repress the expression of others.
Factors that bind DNA don’t always bind unequivocally to the exact same sequence; sometimes they bind a set of sequences that are similar. For instance, a factor may preferably bind AAGCTT, but it may also bind AGGCTT. This understanding led to the concept of  consensus sequences, which means the typical sequence that a factor would most frequently bind, but with the implicit understanding that there may exist some deviations from that particular sequence. In the example above, scientists would say that the consensus sequence for our pretend factor is ‘Aa/gGCTT’.
More often than not, transcription factors bind DNA along with specific partners called ‘co-factors’. In this case, the researchers mapped the binding of known Gata1 cofactors to DNA, but did not find any one in particular that was always co-bound to DNA with Gata1 in mitotic cells.
DNA binds histones, and histones bind each other forming groups of 8 (octamers). ‘Nucleosome’ is the name of DNA bound to one of these histone octamers. In addition, there are linker histones that will bind nucleosomes together. But not all nucleosomes are equally packed; some are more tightly packed, some more loosely, affecting DNA accessibility. The authors suspected (but ruled out) that differential DNA accessibility could be responsible for the binding of Gata1 to some sites and not others.

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