A Simple Grammar Defines Activating and Repressing cis-Regulatory Elements in Photoreceptors

White, Michael A.; Kwasnieski, Jamie C.; Myers, Connie A.; Shen, Susan Q.; Corbo, Joseph C.; Cohen, Barak A.

doi:10.1016/j.celrep.2016.09.066

Cited by 84 publications

(168 citation statements)

References 52 publications

(93 reference statements)

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“…Our results indicate that, with the notable exception of pSTATs, the mere presence or absence of binding motifs for specific TFs cannot predict individual cis-regulatory responses to TPO and raise the possibility that orientation and spacing of TF motifs might play a role in determining these responses. Consistent with this concept, a recent work demonstrated that a different motif grammar based on the same building blocks defines activating and repressing cis-regulatory elements in rod photoreceptors (White et al 2016).…”

Section: Discussionmentioning

confidence: 70%

Thrombopoietin signaling to chromatin elicits rapid and pervasive epigenome remodeling within poised chromatin architectures

et al. 2018

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Thrombopoietin (TPO) is a critical cytokine regulating hematopoietic stem cell maintenance and differentiation into the megakaryocytic lineage. However, the transcriptional and chromatin dynamics elicited by TPO signaling are poorly understood. Here, we study the immediate early transcriptional and cis-regulatory responses to TPO in hematopoietic stem/progenitor cells (HSPCs) and use this paradigm of cytokine signaling to chromatin to dissect the relation between cisregulatory activity and chromatin architecture. We show that TPO profoundly alters the transcriptome of HSPCs, with key hematopoietic regulators being transcriptionally repressed within 30 minutes of TPO. By examining cis-regulatory dynamics and chromatin architectures, we demonstrate that these changes are accompanied by rapid and extensive epigenome remodeling of cis-regulatory landscapes that is spatially coordinated within topologically associating domains (TADs). Moreover, TPO-responsive enhancers are spatially clustered and engage in preferential homotypic intra-and inter-TAD interactions that are largely refractory to TPO signaling. By further examining the link between cis-regulatory dynamics and chromatin looping, we show that rapid modulation of cis-regulatory activity is largely independent of chromatin looping dynamics. Finally, we show that, although activated and repressed cis-regulatory elements share remarkably similar DNA sequence compositions, transcription factor binding patterns accurately predict rapid cis-regulatory responses to TPO.

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Section: Discussionmentioning

confidence: 70%

Thrombopoietin signaling to chromatin elicits rapid and pervasive epigenome remodeling within poised chromatin architectures

et al. 2018

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“…Indeed, several photoreceptor genes are known to be regulated by NRL/CRX co-occupancy within their regulatory regions (Hao et al, 2012; White et al, 2016). Interestingly, a similar co-regulatory function of NRL/CRX appears to hold true in Group 3 MB.…”

Section: Discussionmentioning

confidence: 99%

“…These TFs act in concert during photoreceptor differentiation and synergize to regulate the expression of photoreceptor genes (Hsiau et al, 2007). Consensus binding sites for NRL and CRX often coincide and are enriched in regulatory elements of photoreceptor genes (Hao et al, 2012; White et al, 2016). Knockout of either TF in mice induces strong defects in photoreceptor differentiation and mutations in humans are linked with retinopathies (Swaroop et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma

et al. 2018

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Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities.

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“…Characterization studies examine thousands of different putative regulatory elements that have a wide variety of sequence features and try to correlate these sequence features with measured activity levels (Grossman et al, 2017;Guo et al, 2017;Safra et al, 2017;Levo et al, 2017;Maricque, Dougherty, and Cohen, 2017;Groff et al, 2016;Ernst et al, 2016;White, Kwasnieski, et al, 2016;Ferreira et al, 2016;Fiore and Cohen, 2016;Farley et al, 2015;Kamps-Hughes et al, 2015;Dickel et al, 2014;Kwasnieski, Fiore, et al, 2014;Mogno, Kwasnieski, and Cohen, 2013;Gisselbrecht et al, 2013;White, Myers, et al, 2013;Smith et al, 2013). Typical statistical analyses use regression to study the impact of multiple features simultaneously.…”

Section: Introductionmentioning

confidence: 99%

Linear models enable powerful differential activity analysis in massively parallel reporter assays

Myint

Avramopoulos

Goff

et al. 2017

Preprint

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Massively parallel reporter assays (MPRAs) have emerged as a popular means for understanding noncoding variation in a variety of conditions. However, development of statistical analysis methods has not kept pace with the use of this assay. We present a linear model framework, mpralm, for the differential analysis of activity measures from these experiments that we show is calibrated and powerful. We show that it outperforms statistical tests that are commonly used in the literature, in the first comprehensive evaluation of statistical methods on several datasets. We investigate the theoretical and real-data properties of barcode summarization methods, and show an unappreciated impact of summarization method for some datasets. Finally, we perform a power analysis and show substantial improvements in power by performing up to 6 replicates per condition, whereas sequencing depth has limited impact; we recommend to always use at least 4 replicates. These results inform recommendations for differential analysis, general group comparisons, and power analysis. Our contributions in investigating the functional dependence of statistical power on sample sizes and sequencing depth will help MPRA practitioners make informed choices in study design, and lead to improved inference.

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A Simple Grammar Defines Activating and Repressing cis-Regulatory Elements in Photoreceptors

Cited by 84 publications

References 52 publications

Thrombopoietin signaling to chromatin elicits rapid and pervasive epigenome remodeling within poised chromatin architectures

Thrombopoietin signaling to chromatin elicits rapid and pervasive epigenome remodeling within poised chromatin architectures

NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma

Linear models enable powerful differential activity analysis in massively parallel reporter assays

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