YY1 controls Eμ-3′RR DNA loop formation and immunoglobulin heavy chain class switch recombination

Mehra, Parul; Gerasimova, T. I.; Basu, Arindam; Jha, Vibha; Banerjee, Anupam; Sindhava, Vishal; Gray, Falon; Berry, Corbett T.; Sen, Ranjan; Atchison, Michael L.

doi:10.1182/bloodadvances.2016000372

Cited by 16 publications

(30 citation statements)

References 25 publications

(27 reference statements)

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“…The YY1 protein can also bind RNA [ 25 , 26 ], and the Repeat C region of Xist contains three YY1 binding sites required for tethering Xist RNA to the chromatin of the Xi in post-XCI somatic cells [ 27 ]. YY1 mediates the long-distance DNA interactions required for V(D)J recombination of the immunoglobulin loci and for class switch recombination, and B cell specific YY1 deletion arrests B cell development at the pro-B cell stage [ 28 – 32 ]. We recently found that YY1 deletion or disruption in activated female T and B cells disrupts Xist RNA localization to the Xi with minimal impact on Xist expression [ 33 ], suggesting that YY1 may regulate XCI maintenance through mediating Xist RNA localization in lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells

et al. 2017

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X-chromosome inactivation (XCI) in female lymphocytes is uniquely regulated, as the inactive X (Xi) chromosome lacks localized Xist RNA and heterochromatin modifications. Epigenetic profiling reveals that Xist RNA is lost from the Xi at the pro-B cell stage and that additional heterochromatic modifications are gradually lost during B cell development. Activation of mature B cells restores Xist RNA and heterochromatin to the Xi in a dynamic two-step process that differs in timing and pattern, depending on the method of B cell stimulation. Finally, we find that DNA binding domain of YY1 is necessary for XCI in activated B cells, as ex-vivo YY1 deletion results in loss of Xi heterochromatin marks and up-regulation of X-linked genes. Ectopic expression of the YY1 zinc finger domain is sufficient to restore Xist RNA localization during B cell activation. Together, our results indicate that Xist RNA localization is critical for maintaining XCI in female lymphocytes, and that chromatin changes on the Xi during B cell development and the dynamic nature of YY1-dependent XCI maintenance in mature B cells predisposes X-linked immunity genes to reactivation.

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Section: Introductionmentioning

confidence: 99%

Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells

et al. 2017

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“…Several key NPC-specific enhancer-gene looping interactions were ablated upon Yy1 knockdown. YY1 is an intriguing architectural protein candidate: (1) it is strongly enriched in genome-wide looping interactions in human cell lines (Rao et al 2014); (2) it is necessary for the formation of specific 3D interactions in B cells (Medvedovic et al 2013); (3) it can connect a long-range interaction in B cells in the absence of its transcriptional activation domain (Mehra et al 2016); and (4) it is required for proper neural development (He et al 2007). Future studies should aim to elucidate YY1's function as an architectural protein in non-neural lineages and determine the extent to which YY1's critical role in looping is due to indirect effects on chromatin activity.…”

Section: Wwwgenomeorgmentioning

confidence: 99%

YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment

et al. 2017

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CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here, we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naï ve/primed pluripotency to multipotent primary neural progenitor cells (NPCs). Many pluripotency gene-enhancer interactions are anchored by CTCF, and its occupancy is lost in parallel with loop decommissioning during differentiation. Conversely, CTCF binding sites in NPCs are largely preexisting in pluripotent stem cells. Only a small number of CTCF sites arise de novo in NPCs. We identify another zinc finger protein, Yin Yang 1 (YY1), at the base of looping interactions between NPC-specific genes and enhancers. Putative NPC-specific enhancers exhibit strong YY1 signal when engaged in 3D contacts and negligible YY1 signal when not in loops. Moreover, siRNA knockdown of Yy1 specifically disrupts interactions between key NPC enhancers and their target genes. YY1-mediated interactions between NPC regulatory elements are often nested within constitutive loops anchored by CTCF. Together, our results support a model in which YY1 acts as an architectural protein to connect developmentally regulated looping interactions; the location of YY1-mediated interactions may be demarcated in development by a preexisting topological framework created by constitutive CTCF-mediated interactions.

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“…Specifically, we found that YY1 conditional knock-out ablates the long-distance 220kb DNA loop between the Eμ and 3'RR enhancers believed to be necessary for CSR [43]. We further showed that the YY1 C-terminal half which lacks the transcriptional activation domain is sufficient for controlling this loop [43]. These results indicate that YY1 impacts B cell function by numerous mechanisms including control of gene expression, long-distance DNA loops, and AID stability and nuclear function.…”

Section: Discussionmentioning

confidence: 76%

“…However, we recently found that YY1 also controls other functions that impact CSR. Specifically, we found that YY1 conditional knock-out ablates the long-distance 220kb DNA loop between the Eμ and 3'RR enhancers believed to be necessary for CSR [43]. We further showed that the YY1 C-terminal half which lacks the transcriptional activation domain is sufficient for controlling this loop [43].…”

Section: Discussionmentioning

confidence: 82%

“…Recently, it was shown that activation of Parp1 by DNA damage results in reduced proteasomal degradation of AID, and increased nuclear accumulation [42]. YY1 does not regulate expression of Parp1, but our previous RNA transcript data in LPS plus IL4 activated splenic B cells show that YY1 positively regulates Parp2 expression [43]. Whether YY1 and Parp1 function by the same mechanism to regulate AID nuclear levels is not clear.…”

Section: Discussionmentioning

confidence: 87%

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Transcription factor YY1 can control AID‐mediated mutagenesis in mice

et al. 2017

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Activation-induced cytidine deminase (AID) is crucial for controlling the immunoglobulin (Ig) diversification processes of somatic hypermutation (SHM) and class switch recombination (CSR). AID initiates these processes by deamination of cytosine, ultimately resulting in mutations or double strand DNA breaks needed for SHM and CSR. Levels of AID control mutation rates, and off-target non-Ig gene mutations can contribute to lymphomagenesis. Therefore, factors that control AID levels in the nucleus can regulate SHM and CSR, and may contribute to disease. We previously showed that transcription factor YY1 can regulate the level of AID in the nucleus and Ig CSR. Therefore, we hypothesized that conditional knock-out of YY1 would lead to reduction in AID localization at the Ig locus, and reduced AID-mediated mutations. Using mice that overexpress AID (IgκAID yy1 ) or that express normal AID levels (yy1 ), we found that conditional knock-out of YY1 results in reduced AID nuclear levels, reduced localization of AID to the Sμ switch region, and reduced AID-mediated mutations. We find that the mechanism of YY1 control of AID nuclear accumulation is likely due to YY1-AID physical interaction which blocks AID ubiquitination.

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YY1 controls Eμ-3′RR DNA loop formation and immunoglobulin heavy chain class switch recombination

Abstract: Key Points Transcription factor YY1 regulates the IgH Eμ-3′RR long-distance DNA loop without the YY1 transcriptional activation domain. YY1 constructs that rescue the Eμ-3′RR DNA loop also restore CSR strongly arguing for the necessity of this long-distance DNA loop for CSR.

Cited by 16 publications

References 25 publications

Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells

Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells

YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment

Transcription factor YY1 can control AID‐mediated mutagenesis in mice

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