scholarly journals Independent recruitment of PRC1 and PRC2 by human XIST

2020 ◽  
Author(s):  
Thomas Dixon-McDougall ◽  
Carolyn J. Brown

AbstractXIST establishes inactivation across its chromosome of origin, even when expressed from autosomal transgenes. To identify the regions of human XIST essential for recruiting heterochromatic marks we generated a series of overlapping deletions in an autosomal inducible XIST transgene. We examined the ability of each construct to enrich its unified XIST territory with the histone marks established by PRC1 and PRC2 as well as the heterochromatin factors MacroH2A and SMCHD1. PRC1 recruitment required four distinct regions of XIST, and these were completely distinct from the two domains crucial for PRC2 recruitment. Both the domains required and the impact of inhibitors suggest that PRC1 is required for SMCHD1 while PRC2 function is necessary for MacroH2A recruitment, although incomplete overlap of regions implicates a role for additional factors. The independence of the PRC1/PRC2 pathways, yet important of all regions tested, demonstrate both modularity and cooperativity across the XIST lncRNA.Author SummaryXIST functions as a long, non-protein coding, RNA to initiate various pathways for the silencing of one of the two X chromosomes in female placental mammals. CRISPR-directed mutations of an inducible human XIST construct in somatic cells allowed us to discover which regions of the RNA are required for chromatin modification and protein recruitment. This was the first large-scale dissection of human XIST domains, and every function assessed was dependent on multiple regions of XIST, suggesting considerable interactions between domains of XIST. We observed similarities, but also differences, with the domains previously identified in mouse Xist and demonstrated the presence of independent pathways for chromosome reorganization in humans as well as ascribing new functionality to regions of XIST. The ability of XIST to inactivate large sections of chromosomes from which it is expressed makes it both an exciting potential therapeutic for chromosome number abnormalities as well as a paradigm for how non-coding RNA genes are able to regulate cellular biology.

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Vladislava Chalei ◽  
Stephen N Sansom ◽  
Lesheng Kong ◽  
Sheena Lee ◽  
Juan F Montiel ◽  
...  

Many intergenic long noncoding RNA (lncRNA) loci regulate the expression of adjacent protein coding genes. Less clear is whether intergenic lncRNAs commonly regulate transcription by modulating chromatin at genomically distant loci. Here, we report both genomically local and distal RNA-dependent roles of Dali, a conserved central nervous system expressed intergenic lncRNA. Dali is transcribed downstream of the Pou3f3 transcription factor gene and its depletion disrupts the differentiation of neuroblastoma cells. Locally, Dali transcript regulates transcription of the Pou3f3 locus. Distally, it preferentially targets active promoters and regulates expression of neural differentiation genes, in part through physical association with the POU3F3 protein. Dali interacts with the DNMT1 DNA methyltransferase in mouse and human and regulates DNA methylation status of CpG island-associated promoters in trans. These results demonstrate, for the first time, that a single intergenic lncRNA controls the activity and methylation of genomically distal regulatory elements to modulate large-scale transcriptional programmes.


2021 ◽  
Author(s):  
Hanneke Vlaming ◽  
Claudia A Mimoso ◽  
Benjamin JE Martin ◽  
Andrew R Field ◽  
Karen Adelman

Organismal growth and development rely on RNA Polymerase II (RNAPII) synthesizing the appropriate repertoire of messenger RNAs (mRNAs) from protein-coding genes. Productive elongation of full-length transcripts is essential for mRNA function, however what determines whether an engaged RNAPII molecule will terminate prematurely or transcribe processively remains poorly understood. Notably, despite a common process for transcription initiation across RNAPII-synthesized RNAs, RNAPII is highly susceptible to termination when transcribing non-coding RNAs such as upstream antisense RNAs (uaRNAs) and enhancers RNAs (eRNAs), suggesting that differences arise during RNAPII elongation. To investigate the impact of transcribed sequence on elongation potential, we developed a method to screen the effects of thousands of INtegrated Sequences on Expression of RNA and Translation using high-throughput sequencing (INSERT-seq). We found that higher AT content in uaRNAs and eRNAs, rather than specific sequence motifs, underlies the propensity for RNAPII termination on these transcripts. Further, we demonstrate that 5' splice sites exert both splicing-dependent and autonomous, splicing-independent stimulation of transcription, even in the absence of polyadenylation signals. Together, our results reveal a potent role for transcribed sequence in dictating gene output at mRNA and non-coding RNA loci, and demonstrate the power of INSERT-seq towards illuminating these contributions.


Author(s):  
Uthra Gowthaman ◽  
Desiré García-Pichardo ◽  
Yu Jin ◽  
Isabel Schwarz ◽  
Sebastian Marquardt

RNA polymerase II (RNAPII) frequently transcribes non-protein coding DNA sequences in eukaryotic genomes into long non-coding RNA (lncRNA). Here, we focus on the impact of the act of lncRNA transcription on nearby functional DNA units. Distinct molecular mechanisms linked to the position of lncRNA relative to the coding gene illustrate how non-coding transcription controls gene expression. We review the biological significance of the act of lncRNA transcription on DNA processing, highlighting common themes, such as mediating cellular responses to environmental changes. This review presents the background in chromatin signaling to appreciate examples in different organisms where we can interpret functions of non-coding DNA through the act of RNAPII transcription.


PLoS Genetics ◽  
2021 ◽  
Vol 17 (1) ◽  
pp. e1008761
Author(s):  
Laura Natalia Balarezo-Cisneros ◽  
Steven Parker ◽  
Marcin G. Fraczek ◽  
Soukaina Timouma ◽  
Ping Wang ◽  
...  

Non-coding RNAs (ncRNAs), including the more recently identified Stable Unannotated Transcripts (SUTs) and Cryptic Unstable Transcripts (CUTs), are increasingly being shown to play pivotal roles in the transcriptional and post-transcriptional regulation of genes in eukaryotes. Here, we carried out a large-scale screening of ncRNAs in Saccharomyces cerevisiae, and provide evidence for SUT and CUT function. Phenotypic data on 372 ncRNA deletion strains in 23 different growth conditions were collected, identifying ncRNAs responsible for significant cellular fitness changes. Transcriptome profiles were assembled for 18 haploid ncRNA deletion mutants and 2 essential ncRNA heterozygous deletants. Guided by the resulting RNA-seq data we analysed the genome-wide dysregulation of protein coding genes and non-coding transcripts. Novel functional ncRNAs, SUT125, SUT126, SUT035 and SUT532 that act in trans by modulating transcription factors were identified. Furthermore, we described the impact of SUTs and CUTs in modulating coding gene expression in response to different environmental conditions, regulating important biological process such as respiration (SUT125, SUT126, SUT035, SUT432), steroid biosynthesis (CUT494, SUT053, SUT468) or rRNA processing (SUT075 and snR30). Overall, these data capture and integrate the regulatory and phenotypic network of ncRNAs and protein-coding genes, providing genome-wide evidence of the impact of ncRNAs on cellular homeostasis.


2021 ◽  
Vol 11 ◽  
Author(s):  
Soudeh Ghafouri-Fard ◽  
Tayybeh Khoshbakht ◽  
Bashdar Mahmud Hussen ◽  
Mohammad Taheri ◽  
Majid Mokhtari

AFAP1-AS1 is a long non-coding RNA which partakes in the pathoetiology of several cancers. The sense protein coding gene from this locus partakes in the regulation of cytophagy, cell motility, invasive characteristics of cells and metastatic ability. In addition to acting in concert with AFAP1, AFAP1-AS1 can sequester a number of cancer-related miRNAs, thus affecting activity of signaling pathways involved in cancer progression. Most of animal studies have confirmed that AFAP1-AS1 silencing can reduce tumor volume and invasive behavior of tumor cells in the xenograft models. Moreover, statistical analyses in the human subjects have shown strong correlation between expression levels of this lncRNA and clinical outcomes. In the present work, we review the impact of AFAP1-AS1 in the carcinogenesis.


2020 ◽  
Vol 59 (04) ◽  
pp. 294-299 ◽  
Author(s):  
Lutz S. Freudenberg ◽  
Ulf Dittmer ◽  
Ken Herrmann

Abstract Introduction Preparations of health systems to accommodate large number of severely ill COVID-19 patients in March/April 2020 has a significant impact on nuclear medicine departments. Materials and Methods A web-based questionnaire was designed to differentiate the impact of the pandemic on inpatient and outpatient nuclear medicine operations and on public versus private health systems, respectively. Questions were addressing the following issues: impact on nuclear medicine diagnostics and therapy, use of recommendations, personal protective equipment, and organizational adaptations. The survey was available for 6 days and closed on April 20, 2020. Results 113 complete responses were recorded. Nearly all participants (97 %) report a decline of nuclear medicine diagnostic procedures. The mean reduction in the last three weeks for PET/CT, scintigraphies of bone, myocardium, lung thyroid, sentinel lymph-node are –14.4 %, –47.2 %, –47.5 %, –40.7 %, –58.4 %, and –25.2 % respectively. Furthermore, 76 % of the participants report a reduction in therapies especially for benign thyroid disease (-41.8 %) and radiosynoviorthesis (–53.8 %) while tumor therapies remained mainly stable. 48 % of the participants report a shortage of personal protective equipment. Conclusions Nuclear medicine services are notably reduced 3 weeks after the SARS-CoV-2 pandemic reached Germany, Austria and Switzerland on a large scale. We must be aware that the current crisis will also have a significant economic impact on the healthcare system. As the survey cannot adapt to daily dynamic changes in priorities, it serves as a first snapshot requiring follow-up studies and comparisons with other countries and regions.


2020 ◽  
Vol 6 (5) ◽  
pp. 1183-1189
Author(s):  
Dr. Tridibesh Tripathy ◽  
Dr. Umakant Prusty ◽  
Dr. Chintamani Nayak ◽  
Dr. Rakesh Dwivedi ◽  
Dr. Mohini Gautam

The current article of Uttar Pradesh (UP) is about the ASHAs who are the daughters-in-law of a family that resides in the same community that they serve as the grassroots health worker since 2005 when the NRHM was introduced in the Empowered Action Group (EAG) states. UP is one such Empowered Action Group (EAG) state. The current study explores the actual responses of Recently Delivered Women (RDW) on their visits during the first month of their recent delivery. From the catchment area of each of the 250 ASHAs, two RDWs were selected who had a child in the age group of 3 to 6 months during the survey. The response profiles of the RDWs on the post- delivery first month visits are dwelled upon to evolve a picture representing the entire state of UP. The relevance of the study assumes significance as detailed data on the modalities of postnatal visits are available but not exclusively for the first month period of their recent delivery. The details of the post-delivery first month period related visits are not available even in large scale surveys like National Family Health Survey 4 done in 2015-16. The current study gives an insight in to these visits with a five-point approach i.e. type of personnel doing the visit, frequency of the visits, visits done in a particular week from among those four weeks separately for the three visits separately. The current study is basically regarding the summary of this Penta approach for the post- delivery one-month period.     The first month period after each delivery deals with 70% of the time of the postnatal period & the entire neonatal period. Therefore, it does impact the Maternal Mortality Rate & Ratio (MMR) & the Neonatal Mortality Rates (NMR) in India and especially in UP through the unsafe Maternal & Neonatal practices in the first month period after delivery. The current MM Rate of UP is 20.1 & MM Ratio is 216 whereas the MM ratio is 122 in India (SRS, 2019). The Sample Registration System (SRS) report also mentions that the Life Time Risk (LTR) of a woman in pregnancy is 0.7% which is the highest in the nation (SRS, 2019). This means it is very risky to give birth in UP in comparison to other regions in the country (SRS, 2019). This risk is at the peak in the first month period after each delivery. Similarly, the current NMR in India is 23 per 1000 livebirths (UNIGME,2018). As NMR data is not available separately for states, the national level data also hold good for the states and that’s how for the state of UP as well. These mortalities are the impact indicators and such indicators can be reduced through long drawn processes that includes effective and timely visits to RDWs especially in the first month period after delivery. This would help in making their post-natal & neonatal stage safe. This is the area of post-delivery first month visit profile detailing that the current article helps in popping out in relation to the recent delivery of the respondents.   A total of four districts of Uttar Pradesh were selected purposively for the study and the data collection was conducted in the villages of the respective districts with the help of a pre-tested structured interview schedule with both close-ended and open-ended questions.  The current article deals with five close ended questions with options, two for the type of personnel & frequency while the other three are for each of the three visits in the first month after the recent delivery of respondents. In addition, in-depth interviews were also conducted amongst the RDWs and a total 500 respondents had participated in the study.   Among the districts related to this article, the results showed that ASHA was the type of personnel who did the majority of visits in all the four districts. On the other hand, 25-40% of RDWs in all the 4 districts replied that they did not receive any visit within the first month of their recent delivery. Regarding frequency, most of the RDWs in all the 4 districts received 1-2 times visits by ASHAs.   Regarding the first visit, it was found that the ASHAs of Barabanki and Gonda visited less percentage of RDWs in the first week after delivery. Similarly, the second visit revealed that about 1.2% RDWs in Banda district could not recall about the visit. Further on the second visit, the RDWs responded that most of them in 3 districts except Gonda district did receive the second postnatal visit in 7-15 days after their recent delivery. Less than half of RDWs in Barabanki district & just more than half of RDWs in Gonda district received the third visit in 15-21 days period after delivery. For the same period, the majority of RDWs in the rest two districts responded that they had been entertained through a home visit.


e-Finanse ◽  
2018 ◽  
Vol 14 (4) ◽  
pp. 67-76
Author(s):  
Piotr Bartkiewicz

AbstractThe article presents the results of the review of the empirical literature regarding the impact of quantitative easing (QE) on emerging markets (EMs). The subject is of interest to policymakers and researchers due to the increasingly larger role of EMs in the world economy and the large-scale capital flows occurring after 2009. The review is conducted in a systematic manner and takes into consideration different methodological choices, samples and measurement issues. The paper puts the summarized results in the context of transmission channels identified in the literature. There are few distinct methodological approaches present in the literature. While there is a consensus regarding the direction of the impact of QE on EMs, its size and durability have not yet been assessed with sufficient precision. In addition, there are clear gaps in the empirical findings, not least related to relative underrepresentation of the CEE region (in particular, Poland).


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