Memories of lost enhancers: Figure 1.

Sen, Ranjan; Grosschedl, Rudolf

doi:10.1101/gad.1930610

Cited by 19 publications

(20 citation statements)

References 48 publications

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“…While it seems clear that enhancers are required to initiate an active chromatin state, whether they are required continuously to maintain the active state once established is an interesting question (13). This question has been addressed in the human ␤-globin locus and mouse IgH gene by deleting these genes' locus control region, intronic E or far downstream enhancers.…”

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confidence: 99%

Loss of an Igκ Gene Enhancer in Mature B Cells Results in Rapid Gene Silencing and Partial Reversible Dedifferentiation

Zhou

Xiang

Ding

et al. 2013

Molecular and Cellular Biology

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bWe address here whether there is cellular memory of a transcriptional enhancer once it has served its purpose to establish an active chromatin state. We have previously shown that the mouse Ig gene's downstream enhancers, E3= and Ed, are essential but play redundant roles for establishing transcriptional activity in the locus during B cell development. To determine whether these enhancers are also necessary for the maintenance of transcriptional activity, we conditionally deleted E3= in mature B cells that possessed Ed ؊/؊ alleles. Upon E3= deletion, the locus became rapidly silenced and lost positive histone epigenetic marks, and the mature B cells partially dedifferentiated, induced RAG-1 and -2 along with certain other pro-B cell makers, and then redifferentiated after triggering Ig gene rearrangements. We conclude that the Ig gene's downstream enhancers are essential for both the establishment and maintenance of transcriptional activity and that there is no cellular memory of previous transcriptional activity in this locus. Furthermore, upon enhancer loss, the mature B cells unexpectedly underwent reversible retrograde differentiation. This result establishes that receptor editing can occur in mature B cells and raises the possibility that this may provide a tolerance mechanism for eliminating autoreactive B cells in the periphery. During B cell development, the mouse IgH and IgL loci become activated in a stepwise fashion for gene rearrangement (1). The IgH gene rearranges first, by sequential D-J and then by V-(D)J joining, leading to the pro-and pre-B cell stages of development, respectively. The Ig locus undergoes rearrangement next in pre-B cells, where a V gene is joined to a J region. If Ig V-J joining is productively unsuccessful because of out-of-reading frame recombination junctions, then the Ig locus becomes activated for rearrangement and expression, which in wild-type (WT) mice accounts for production of only approximately 5% of the total IgL chains (2).In order to characterize chromatin structure-function relationships in a model system, research in our laboratory has focused on the mouse Ig locus because it offers the opportunity to identify changes in chromatin structure that may precede gene rearrangement and transcriptional activation during B lymphocyte differentiation, as well as to visualize chromatin remodeling events that are linked to gene activation (reference 3 and references therein). Rearrangement of the Ig locus deposits a V gene carrying its own promoter into a chromatin domain containing three powerful enhancers: an intronic enhancer (Ei) within the transcription unit (4), and two enhancers downstream of the transcription termination region, termed E3= and Ed (3, 5). The results of chromosome conformation capture experiments have revealed that in activated B cells, the three enhancers exhibit all possible pairwise interactions with themselves and rearranged V gene promoters, with the looping out of the intervening DNA sequences (6). However, in unstimulated B cells, rearranged...

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confidence: 99%

Loss of an Igκ Gene Enhancer in Mature B Cells Results in Rapid Gene Silencing and Partial Reversible Dedifferentiation

Zhou

Xiang

Ding

et al. 2013

Molecular and Cellular Biology

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“…The enhancer region is also an inflection point for H3K36 methylation, but that occurs in both cell types. In a recent review, the still enigmatic role of enhancers in maintenance and memory of transcriptional activation was explored (30). The enhancer (E) between the Vh regions and Ch regions was the first transcriptional enhancer discovered (31), yet its mechanism of action remains obscure.…”

Section: Discussionmentioning

confidence: 99%

The Eleven-Nineteen Lysine-rich Leukemia Gene (ELL2) Influences the Histone H3 Protein Modifications Accompanying the Shift to Secretory Immunoglobulin Heavy Chain mRNA Production

Milcarek

Albring

Langer

et al. 2011

Journal of Biological Chemistry

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“…In addition, there are data strongly suggesting that mammalian enhancers change the positions of nucleosomes in the surrounding chromatin [12]. Interestingly, after the removal of the enhancer, active transcription may be retained because the chromatin modifications are retained at the site of the enhancer (the so called transcriptional memory) [13,14]. This strongly suggests that the epigenetic mechanisms are the key in the functioning of enhancers.…”

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confidence: 97%

Molecular analysis of enhancer RNAs and chromatin modifications in the region of their synthesis in Drosophila cells possessing genetic constructs

Федосеева

Kretova

Tchurikov

2012

Dokl Biochem Biophys

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Memories of lost enhancers: Figure 1.

Cited by 19 publications

References 48 publications

Loss of an Igκ Gene Enhancer in Mature B Cells Results in Rapid Gene Silencing and Partial Reversible Dedifferentiation

Loss of an Igκ Gene Enhancer in Mature B Cells Results in Rapid Gene Silencing and Partial Reversible Dedifferentiation

The Eleven-Nineteen Lysine-rich Leukemia Gene (ELL2) Influences the Histone H3 Protein Modifications Accompanying the Shift to Secretory Immunoglobulin Heavy Chain mRNA Production

Molecular analysis of enhancer RNAs and chromatin modifications in the region of their synthesis in Drosophila cells possessing genetic constructs

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