High-Throughput Discovery and Characterization of Human Transcriptional Effectors

Tycko, Josh; DelRosso, Nicole; Hess, Gaelen T.; Aradhana,; Banerjee, Abhimanyu; Mukund, Adi; Van, Mike V.; Ego, Braeden K.; Yao, David; Spees, Kaitlyn; Suzuki, Peter; Marinov, Georgi K.; Kundaje, Anshul; Bassik, Michael C.; Bintu, Lacramioara

doi:10.1016/j.cell.2020.11.024

Cited by 93 publications

(212 citation statements)

References 98 publications

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“…In addition, IPA analysis also indicated mitochondrial dysfunction, which contributes to cartilage/meniscus cell apoptosis (indicated by increased cleaved caspase 3) and degradation of joints 40 , 41 . Mitochondrial dysfunction within the menisci after spaceflight is also in agreement with altered mitochondrial dysfunction and stress observed during and after spaceflight from multiple rodent tissues and astronauts 24 These molecular and phenotypic responses in the menisci are similar in nature to the response observed in the knee and hip articular cartilage from female mice after 30 days of HLU 16 . Similar catabolic mechanisms and responses have also been observed in other in vitro and in vivo osteoarthritic models, with increased oxidative stress, reduced anabolic pathways, and evidence of mitochondrial dysfunction 42 – 47 .…”

Section: Discussionsupporting

confidence: 76%

“…Rodents exposed to microgravity in spaceflight experience reduced weight-bearing across joints without the full knee joint immobilization typical of preclinical studies 22 , representing a unique model to study joint tissue responses to unloading. Rapid bone loss and muscle wasting in both rodents and astronauts are well-documented consequences of the skeletal disuse that occurs during periods of microgravity 23 , 24 . Limited data exist regarding rodent joint responses to spaceflight.…”

Section: Introductionmentioning

confidence: 99%

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Spaceflight and hind limb unloading induces an arthritic phenotype in knee articular cartilage and menisci of rodents

Kwok

Mohamed

Plate

et al. 2021

Sci Rep

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Reduced knee weight-bearing from prescription or sedentary lifestyles are associated with cartilage degradation; effects on the meniscus are unclear. Rodents exposed to spaceflight or hind limb unloading (HLU) represent unique opportunities to evaluate this question. This study evaluated arthritic changes in the medial knee compartment that bears the highest loads across the knee after actual and simulated spaceflight, and recovery with subsequent full weight-bearing. Cartilage and meniscal degradation in mice were measured via microCT, histology, and proteomics and/or biochemically after: (1) ~ 35 days on the International Space Station (ISS); (2) 13-days aboard the Space Shuttle Atlantis; or (3) 30 days of HLU, followed by a 49-day weight-bearing readaptation with/without exercise. Cartilage degradation post-ISS and HLU occurred at similar spatial locations, the tibial-femoral cartilage-cartilage contact point, with meniscal volume decline. Cartilage and meniscal glycosaminoglycan content were decreased in unloaded mice, with elevated catabolic enzymes (e.g., matrix metalloproteinases), and elevated oxidative stress and catabolic molecular pathway responses in menisci. After the 13-day Shuttle flight, meniscal degradation was observed. During readaptation, recovery of cartilage volume and thickness occurred with exercise. Reduced weight-bearing from either spaceflight or HLU induced an arthritic phenotype in cartilage and menisci, and exercise promoted recovery.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Spaceflight and hind limb unloading induces an arthritic phenotype in knee articular cartilage and menisci of rodents

Kwok

Mohamed

Plate

et al. 2021

Sci Rep

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“…In fact, there is increasing evidence that the homeodomain itself can be a large driver of transcriptional repression, and that the extent of this repression is paralog specific. A recent study quantitively measured protein domain transcriptional activity using a novel high-throughput sequencing technique, HT-recruit ( Tycko et al, 2020 ). This study fused a large library of TF protein domains to the rTetR DNA binding domain within a lentivirus and assessed their ability to alter a citrine reporter gene under the control of TetO binding sites.…”

Section: Hox Factors As Multi-functional Transcriptional Activators and Repressorsmentioning

confidence: 99%

“…After subjecting infected cells to doxycycline, cells were sorted for citrine-ON versus citrine-OFF and the read count ratio between the off and on cells was used to quantify the repression capability of each protein domain. Through this technique, they discovered that the repression capability of the Hox homeodomains was colinear and correlated with paralog such that posterior Hox factors had a more potent repression activity than the anterior Hox factors ( Tycko et al, 2020 ). The authors then connected the enhanced repression of posterior factors to a more positively charged N-terminal arm in the homeodomain, specifically a RKKR motif ( Tycko et al, 2020 ).…”

Section: Hox Factors As Multi-functional Transcriptional Activators and Repressorsmentioning

confidence: 99%

Mechanisms Underlying Hox-Mediated Transcriptional Outcomes

Cain

Gebelein

2021

Front. Cell Dev. Biol.

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Metazoans differentially express multiple Hox transcription factors to specify diverse cell fates along the developing anterior-posterior axis. Two challenges arise when trying to understand how the Hox transcription factors regulate the required target genes for morphogenesis: First, how does each Hox factor differ from one another to accurately activate and repress target genes required for the formation of distinct segment and regional identities? Second, how can a Hox factor that is broadly expressed in many tissues within a segment impact the development of specific organs by regulating target genes in a cell type-specific manner? In this review, we highlight how recent genomic, interactome, and cis-regulatory studies are providing new insights into answering these two questions. Collectively, these studies suggest that Hox factors may differentially modify the chromatin of gene targets as well as utilize numerous interactions with additional co-activators, co-repressors, and sequence-specific transcription factors to achieve accurate segment and cell type-specific transcriptional outcomes.

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“…In particular, two sites were identified positively selected, beneficial mutations: 227V (prob ~ 0.98) and 252M (prob ~ 0.96, naive empirical bayes, reference: human full-length aa sequence). While 252M is typically not well conserved in other KRAB domains, and its functional relevance is unknown, position 227 is a well conserved F in other in other KRAB domains, and is important for binding the transposable element suppressor TRIM28 70,71 . We conclude that the gene is functional and mostly under purifying selection but in one subregion in some lineages it is functional and subject to positive selection for reasons unknown.…”

Section: Pgbd1 Is Commonly Under Purifying Selectionmentioning

confidence: 99%

PiggyBac Transposable Element-derived 1 controls Neuronal Progenitor Identity, Stress Sensing and mammal-specific paraspeckles

Raskó

Pande

Radscheit

et al. 2021

Preprint

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The evolution and functional integration of new genes, especially those that become core to key functions, remains enigmatic. We consider the mammal-specific gene, piggyBac transposable element derived 1 (PGBD1), implicated in neuronal disorders. While it no longer recognises piggyBac transposon-like inverted repeats and transposase functionality having been lost, it has evolved a core role in neural homeostasis. Depletion of PGBD1 triggers accumulation of mammal-specific paraspeckles and neural differentiation. It acts by two modalities, DNA binding and protein-protein interaction. As a transcriptional repressor of (lnc)NEAT1, the backbone of paraspeckles, it inhibits paraspeckle formation in neural progenitor cells (NPCs). At the protein level it is associated with the stress response system, a function partially shared with (lnc)NEAT1. PGBD1 thus presents as an unusual exemplar of new gene creation, being a recently acquired multi-function, multi-modal gene. Mammalian specificity associated with control of a mammal-specific structure implies coevolution of new genes with new functions.

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High-Throughput Discovery and Characterization of Human Transcriptional Effectors

Cited by 93 publications

References 98 publications

Spaceflight and hind limb unloading induces an arthritic phenotype in knee articular cartilage and menisci of rodents

Spaceflight and hind limb unloading induces an arthritic phenotype in knee articular cartilage and menisci of rodents

Mechanisms Underlying Hox-Mediated Transcriptional Outcomes

PiggyBac Transposable Element-derived 1 controls Neuronal Progenitor Identity, Stress Sensing and mammal-specific paraspeckles

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