LADL: light-activated dynamic looping for endogenous gene expression control

Kim, Ji Hun; Rege, Mayuri; Valeri, Jacqueline A.; Dunagin, Margaret C.; Metzger, Aryeh; Titus, Katelyn R.; Gilgenast, Thomas G.; Gong, Wanfeng; Beagan, Jonathan A.; Raj, Arjun; Phillips-Cremins, Jennifer E.

doi:10.1038/s41592-019-0436-5

Cited by 114 publications

(77 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Catalytic or domain mutations can be combined with TF bypass experiments to further narrow down specific cofactor functions, such as SUV39H1 binding to H3K9me3, necessary for restructuring the genome (Wijchers et al, 2016). In addition, dCas9 and other DNA binding domains have been used to perturb specific aspects of 3D genome organization (Kim et al, 2019a;Morgan et al, 2017;Pollex and Heard, 2019;Reddy et al, 2008;Wang et al, 2018;Wijchers et al, 2016), and could be used to study their effects on TF function.…”

Section: Outlook and Future Directionsmentioning

confidence: 99%

Mechanisms of Interplay between Transcription Factors and the 3D Genome

2019

View full text Add to dashboard Cite

Transcription factors (TFs) bind DNA in a sequence-specific manner and thereby serve as the protein anchors and determinants of 3D genome organization. Conversely, chromatin conformation shapes TF activity, for example by looping TF-bound enhancers to distally located target genes. Despite considerable effort, our understanding of the mechanistic relationship between TFs and 3D genome organization remains limited, in large part due to this interdependency. In this review, we summarize the evidence for the diverse mechanisms by which TFs and their activity shape the 3D genome, and vice versa. We further highlight outstanding questions and potential approaches for untangling the complex relationship between TF activity and the 3D genome.

show abstract

Section: Outlook and Future Directionsmentioning

confidence: 99%

Mechanisms of Interplay between Transcription Factors and the 3D Genome

2019

View full text Add to dashboard Cite

show abstract

“…Enhancers are frequently found to be positioned close to their target gene promoters in 3D space at the time of gene activation, suggesting a role for the chromatin architecture in gene regulation 6, 7 . Indeed, artificially induced spatial proximity between enhancers and promoters has been shown to lead to gene activation 8, 9 . Insulators, on the other hand, act to block enhancer-promoter contacts to prevent ectopic gene activation 10–12 .…”

Section: Introductionmentioning

confidence: 99%

CTCF Promotes Long-range Enhancer-promoter Interactions and Lineage-specific Gene Expression in Mammalian Cells

Kubo¹,

Ishii²,

Xiong

et al. 2020

Preprint

View full text Add to dashboard Cite

23 24 [All datasets have been deposited to GEO, with accession number GSE94452, and can be 25 accessed here]. 26 3 Abstract: 27 Topologically associating domains (TAD) and insulated neighborhoods (INs) have been 28 proposed to constrain enhancer-promoter communications to enable cell-type specific 29 transcription programs, but recent studies show that disruption of TADs and INs resulted in 30 relatively mild changes in gene expression profiles. To better understand the role of 31 chromatin architecture in dynamic enhancer-promoter contacts and lineage-specific gene 32 expression, we have utilized the auxin-inducible degron system to acutely deplete CTCF, a 33 key factor involved in TADs and IN formation, in mouse embryonic stem cells (mESCs) and 34 examined chromatin architecture and gene regulation during neural differentiation. We find 35 that while CTCF depletion leads to global weakening of TAD boundaries and loss of INs, only 36 a minor fraction of enhancer-promoter contacts are lost, affecting a small subset of genes. 37 The CTCF-dependent enhancer-promoter contacts tend to be long-range, spanning hundreds 38 of kilobases, and are established directly by CTCF binding to promoters. Disruption of CTCF 39 binding at the promoter reduces enhancer-promoter contacts and transcription, while 40 artificial tethering of CTCF to the promoter restores the enhancer-promoter contacts and 41 gene activation. Genome-wide analysis of CTCF binding and gene expression across multiple 42 mouse tissues suggests that CTCF-dependent promoter-enhancer contacts may regulate 43 4 expression of additional mouse genes, particularly those expressed in the brain. Our results 44 uncover both CTCF-dependent and independent enhancer-promoter contacts, and highlight a 45 distinct role for CTCF in promoting enhancer-promoter contacts and gene activation in 46 addition to its insulator function. 47 48 5 Introduction: 49Transcriptional regulation in mammalian cells is orchestrated by cis-regulatory elements that include 50 promoters, enhancers, insulators and other less well characterized sequences 1,2 . Large-scale 51 projects such as ENCODE have annotated millions of candidate cis-regulatory elements in the 52 human genome and genomes of other mammalian species 3-5 . A majority of these candidate 53 regulatory elements are located far from transcription start sites(i.e. promoters), display tissue and 54 cell-type specific chromatin accessibility, and likely act as enhancers to regulate cell-type specific 55 gene expression. Enhancers are frequently found to be positioned close to their target gene 56 promoters in 3D space at the time of gene activation, suggesting a role for the chromatin 57 architecture in gene regulation 6,7 . Indeed, artificially induced spatial proximity between enhancers 58 and promoters has been shown to lead to gene activation 8,9 . Insulators, on the other hand, act to 59 block enhancer-promoter contacts to prevent ectopic gene activation 10-12 . Clearly, in-depth 60 knowledge of the chromatin architecture in each...

show abstract

“…Recent work from Phillips‐Cremins and co‐workers on blue light inducible chromatin loops revealed that association between the promoter of gene Zfp462 and a stretch enhancer for gene Klf4 resulted in upregulation of ZFP462 expression. [ 108 ] In this vein, loss of mechanical tension on a GOI below a threshold could enable long‐range association of the GOI with a distant enhancer and result in transcriptional upregulation. In contrast, increasing tension on such a chromatin segment could serve to inhibit the formation of this gene activating loop, demonstrating the reversibility of such a process.…”

Section: Mechanical Memories May Be Stored In the Epigenome And Chrommentioning

confidence: 99%

“Looping In” Mechanics: Mechanobiologic Regulation of the Nucleus and the Epigenome

Dai

Heo

Mauck

2020

Adv Healthcare Materials

View full text Add to dashboard Cite

cues, or "mechanical memory," results from the stable remodeling of various components of the cell. Defining of the mechanisms by which the cell forms and maintains mechanical memories will forward the development of new biomaterials with improved cell functionality. Importantly, converging strands of evidence have implicated the cell nucleus, the storehouse of the genome, as a critically important adaptive mechanosensor in all cells. [2,3] In particular, recent evidence has shown that forces can be directly transmitted to chromatin to alter gene expression. [4] In this review, we discuss the central importance of the cell nucleus and chromatin in understanding and manipulating mechanobiological pathways, and the manner in which extracellular mechanical cues are "looped in" (that is, transmitted to, interpreted by, and stored in) the epigenome and chromatin organization to direct cell fate. In Section 2, we define a framework for understanding how cells sense, transduce, and remember mechanical cues. In Section 3, we provide an overview of how the cell nucleus senses, transduces and adapts to mechanical forces. Following this, we describe in Section 4 how mechanical memories might be encoded within organized chromatin through molecular signaling as well as direct force-induced structural rearrangements. Finally, we conclude in Section 5, outlining new directions for the field in reducing this new knowledge to practice. Mechanotransduction and Mechanical MemoryIn this section, we review the concepts of mechanotransduction and mechanical memory in the mammalian cell. MechanotransductionThe last decade has witnessed a number of technological advances that enable the study of cell mechanics down to the sub-protein level, fostering a new understanding of the role of mechanobiological mechanisms in governing cell behavior (for a comprehensive overview of this topic, please refer to the following reviews [5,6] ). Indeed, it is now well accepted that mechanical cues play a fundamental role in directing cell behavior. Cells sense exogenous mechanical forces in addition to exerting their own. These processes are accomplished through the mechanobiological machinery of the cell-the force sensing (e.g., integrin based focal adhesions), [7] transmitting Cells respond to physical cues in their microenvironment. These cues result in changes in cell behavior, some of which are transient, and others of which are permanent. Understanding and leveraging permanent alteration of cell behavior induced by mechanical cues, or "mechanical memories," is an important aim in cell and tissue engineering. Herein, this paper reviews the existing literature outlining how cells may store memories of biophysical cues with a specific focus on the nucleus, the storehouse of information in eukaryotic cells. In particular, this review details mechanically driven adaptations in nuclear structure and genome organization and outlines potential mechanisms by which mechanical memories may be encoded within the structure and organization of the nucleus and ...

show abstract

LADL: light-activated dynamic looping for endogenous gene expression control

Cited by 114 publications

References 28 publications

Mechanisms of Interplay between Transcription Factors and the 3D Genome

Mechanisms of Interplay between Transcription Factors and the 3D Genome

CTCF Promotes Long-range Enhancer-promoter Interactions and Lineage-specific Gene Expression in Mammalian Cells

“Looping In” Mechanics: Mechanobiologic Regulation of the Nucleus and the Epigenome

Contact Info

Product

Resources

About