ENL initiates multivalent phase separation of the super elongation complex (SEC) in controlling rapid transcriptional activation

Guo, Chenghao; Che, Zhuanzhuan; Yue, Junjie; Xie, Peng; Hao, Shaohua; Xie, Wei; Luo, Zhuojuan; Lin, Chengqi

doi:10.1126/sciadv.aay4858

Cited by 60 publications

(78 citation statements)

References 48 publications

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“…In this regard, we note that some human transcription factors include long polyglycine tracts. Human transcription is highly dependent on hydrogel (LLPS) compartments [13][14][15]18]. One example is the human androgen receptor, which includes a Gly23 tract.…”

Section: Polyglycine Worldmentioning

confidence: 99%

“…For instance, LLPS compartments tend to be larger and easier to visualize in eukaryotic systems. As a critical phase of their evolution, Eukaryotes appear to have powerfully enriched LLPS systems by increasing the use of proteins that include intrinsically disordered regions with the potential for covalent modification and non-covalent bonding of diverse hydrogel components [13][14][15]17,18,32,33,132]. Examples of intrinsically disordered regions with these properties include histone tails and the carboxy-terminal domain of RNA polymerase II.…”

Section: Polyglycine World (A Working Model)mentioning

confidence: 99%

“…For instance, as RNA polymerase II traverses the transcription cycle, polymerase can move between LLPS compartments that support different phases of the cycle. Transcriptional super-enhancers that direct cell-specific gene regulation programs organize hydrogel compartments, and, in some cancers, super-enhancers become disorganized and sometimes fuse together [15,17]. The nucleolis is a hydrogel compartment for RNA polymerase I transcription and ribosome assembly [134].…”

Section: Polyglycine World (A Working Model)mentioning

confidence: 99%

“…Subsequently, another endosymbiotic event involving a cyanobacterium invading an alga gave rise to plants. Evolution of animal complexity required evolution of a promoter-proximal pausing mechanism of RNA polymerase II and the RNA polymerase II CTD (carboxy-terminal domain) [13][14][15]. The best descriptions of the key stages relate to evolution of biological coding, translation and transcriptional mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…It appears that Eukarya evolved a new use for hydrogels (liquid-liquid phase separation; LLPS) involving intrinsically disordered regions (IDRs) of proteins [13,17,32,33]. Histone tails and the carboxy-terminal domain (CTD) of RNA polymerase II are IDRs with regulated interactions and protein readers [13][14][15]. Other factors with IDRs cooperate in the transcription cycle, sequestering complexes in LLPS compartments.…”

Section: Introductionmentioning

confidence: 99%

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Chaos, Order and Systematics in Evolution of The Genetic Code

Lei¹,

Burton²

2020

Preprint

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The genetic code evolved by a combination of chaotic and ordered processes. Liquid-liquid phase separation (hydrogels), a chaotic process, constructs diverse membraneless compartments within cells, resulting in regulated hydration and sequestration and concentration of reaction components. Hydrogels relate to chaotic amyloid fiber production. We propose that polyglycine and related hydrogels (i.e. GADV; G is glycine), phase separations, membraneless droplets and amyloid accretions organized protocell domains to drive the earliest evolution of the genetic code and the pre-life to cellular life transition. By contrast, evolution of tRNA, tRNAomes, aminoacyl-tRNA synthetases and translation systems followed highly ordered and systematic pathways, described by well-defined mechanisms and rules. The pathway of evolution of aminoacyl-tRNA synthetases, which tracked evolution of the genetic code, is clarified. Hydrogels and amyloids form a chaotic component, therefore, that complemented otherwise systematic processes. We describe with detail a pre-life world in which hydrogels and amyloids provided the Darwinian selections of the first life.

show abstract

Section: Polyglycine Worldmentioning

confidence: 99%

Section: Polyglycine World (A Working Model)mentioning

confidence: 99%

Section: Polyglycine World (A Working Model)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chaos, Order and Systematics in Evolution of The Genetic Code

Lei¹,

Burton²

2020

Preprint

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The Mediator subunit MED12 promotes formation of HSF1 condensates on heat shock response element arrays in heat‐shocked cells

et al. 2023

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Upon heat shock, activated heat shock transcription factor 1 (HSF1) binds to the heat shock response elements (HSEs) in the promoters of mammalian heat shock protein (HSP)-encoding genes and recruits the preinitiation complex and coactivators, including Mediator. These transcriptional regulators may be concentrated in phase-separated condensates around the promoters, but they are too minute to be characterized in detail. We herein established HSF1 À/À mouse embryonic fibroblasts harbouring HSP72-derived multiple HSE arrays and visualized the condensates of fluorescent protein-tagged HSF1 with liquid-like properties upon heat shock. Using this experimental system, we demonstrate that endogenous MED12, a subunit of Mediator, is concentrated in artificial HSF1 condensates upon heat shock. Furthermore, the knockdown of MED12 markedly reduces the size of condensates, suggesting an important role for MED12 in HSF1 condensate formation.

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cAMP‐Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease

Song

Wang

et al. 2022

Advanced Science

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Formation of biomolecular condensates by phase separation has recently emerged as a new principle for regulating gene expression in response to extracellular signaling. However, the molecular mechanisms underlying the coupling of signal transduction and gene activation through condensate formation, and how dysregulation of these mechanisms contributes to disease progression, remain elusive. Here, the authors report that CREB-regulated transcription coactivator 2 (CRTC2) translocates to the nucleus and forms phase-separated condensates upon activation of cAMP signaling. They show that intranuclear CRTC2 interacts with positive transcription elongation factor b (P-TEFb) and activates P-TEFb by disrupting the inhibitory 7SK snRNP complex. Aberrantly elevated cAMP signaling plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD). They find that CRTC2 localizes to the nucleus and forms condensates in cystic epithelial cells of both mouse and human ADPKD kidneys. Genetic depletion of CRTC2 suppresses cyst growth in an orthologous ADPKD mouse model. Using integrative transcriptomic and cistromic analyses, they identify CRTC2-regulated cystogenesis-associated genes, whose activation depends on CRTC2 condensate-facilitated P-TEFb recruitment and the release of paused RNA polymerase II. Together, their findings elucidate a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and thereby promotes cystogenesis in ADPKD.

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ENL initiates multivalent phase separation of the super elongation complex (SEC) in controlling rapid transcriptional activation

Cited by 60 publications

References 48 publications

Chaos, Order and Systematics in Evolution of The Genetic Code

Chaos, Order and Systematics in Evolution of The Genetic Code

The Mediator subunit MED12 promotes formation of HSF1 condensates on heat shock response element arrays in heat‐shocked cells

cAMP‐Induced Nuclear Condensation of CRTC2 Promotes Transcription Elongation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease

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