The primate-specific noncoding RNA HPAT5 regulates pluripotency during human preimplantation development and nuclear reprogramming

Durruthy-Durruthy, Jens; Sebastiano, Vittorio; Wossidlo, Mark; Cepeda, Diana A; Cui, Jun; Grow, Edward J.; Davila, Jonathan; Mall, Moritz; Wong, Wing Hung; Wysocka, Joanna; Au, Kin Fai; Pera, Renee A. Reijo

doi:10.1038/ng.3449

Cited by 153 publications

(164 citation statements)

References 55 publications

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“…One strategy which ensures complete ablation would be to delete the entire genomic region associated with a lncRNA. For example, deletion of the 6kb lncRNA HPAT5 in pluripotent stem cells revealed a critical role for this lncRNA in pluripotency and primate preimplantation development [46]. This approach has been highly effective and expanded to create highly informative genome-wide scales of lncRNA depletion screens [47].…”

Section: Determining Function Using Genome and Epigenome Editing Toolsmentioning

confidence: 99%

The emerging molecular biology toolbox for the study of long noncoding RNA biology

et al. 2017

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Long noncoding RNAs (lncRNAs) have been implicated in many biological processes. However, due to the unique nature of lncRNAs and the consequential difficulties associated with their characterization, there is a growing disparity between the rate at which lncRNAs are being discovered and the assignment of biological function to these transcripts. Here we present a molecular biology toolbox equipped to help dissect aspects of lncRNA biology and reveal functionality. We outline an approach that begins with a broad survey of genome-wide, high-throughput datasets to identify potential lncRNA candidates and then narrow the focus on specific methods that are well suited to interrogate the transcripts of interest more closely. This involves the use of imaging-based strategies to validate these candidates and observe the behaviors of these transcripts at single molecule resolution in individual cells. We also describe the use of gene editing tools and interactome capture techniques to interrogate functionality and infer mechanism, respectively. With the emergence of lncRNAs as important molecules in healthy and diseased cellular function, it remains crucial to deepen our understanding of their biology. One of the greatest challenges in modern day genomics is ascribing function to genes and genetic elements. It has become apparent that most of the human genome is pervasively transcribed, but less than 2% of these outputs are putatively functional RNAs that encode for proteins [1][2][3][4]. The functions of the remaining proportion of the transcriptome and the genomic regions from which they arise, mostly remain uncharacterized and make up the 'dark matter' of the genome. With the advent and development of RNA deep sequencing technologies, long noncoding RNAs (lncRNAs) have been revealed to emanate from these dark regions of the genome [5]. For a long time, the biological utility of these transcripts remained unknown and highly controversial, with many believing that they were functionless due to their lack of any protein-coding potential. In short, they were thought to simply be the result of transcriptional noise. This skepticism was further compounded by evidence pointing to the poor specificity of RNA PolII binding and transcription initiation, their low abundance and poor conservation [6][7][8]. However, over the last decade, several examples of well-studied lncRNAs have been identified that show they are indeed functional molecules and play important roles in many biological processes [5].LncRNAs are generally products of RNA PolII activity and are arbitrarily defined as being greater than 200 nucleotides in length [9]. These transcripts can arise from genomic regions that intervene (lincRNAs) or are within protein-coding genes (i.e., introns, overlapping exons, antisense transcripts) as well as enhancer regions and promoter regions [5]. Nascent lncRNA transcripts undergo post-transcriptional modifications resulting in products that are capped at the 5 -end and often spliced and polyadenylated [9]. Furthermore, cert...

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Section: Determining Function Using Genome and Epigenome Editing Toolsmentioning

confidence: 99%

The emerging molecular biology toolbox for the study of long noncoding RNA biology

et al. 2017

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“…WDR5 itself needs the binding of specific lnc-RNAs essential to maintain this active chromatin state [123]. Recently, a primate-specific lnc-RNA HPAT5 was identified to be an integral regulator of pluripotency in preimplantation development [124]. Further untangling of the relationship of non-coding RNA and the epigenomic machinery will undoubtedly reveal detailed molecular mechanisms in species-specific function.…”

Section: Insights From the Interplay Of The Epigenome And Long Non-comentioning

confidence: 99%

Insights in human epigenomic dynamics through comparative primate analysis

Bell

2016

Genomics

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Epigenomic analysis gives a molecular insight into cell-specific genomic activity. It provides a detailed functional plan to dissect an organism, tissue by tissue.Therefore comparative epigenomics may increase understanding of human-acquired traits, by revealing regulatory changes in systems such as the neurological, musculoskeletal, and immunological.Enhancer loci evolve fast by hijacking elements from other tissues or rewiring and amplifying existing units for human-specific function. Promoters by contrast often require a CpG dense genetic infrastructure. Specific interplay occurs between the two, but also a shared modality of function, with coordination from global chromatin-modifying enzymes. Changes in specific transcription factor binding sites also facilitate the local epigenetic state. In the case of CTCF, these may further influence 3-dimensional structure and interaction.How these mechanistic units are modulated between tissue and species enables more comprehensive understanding of human processes and pathology.With this, precise therapeutic targeting of these epigenetic modifications may become possible.

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“…For example, it has been reported that Sall4, Nanog, Esrrb, and Lin28 better recapitulated an ES expressional network than Oct4, Sox2, Klf4, and c-Myc [14]. Genomic-scale analyses have also shown that both miRs and large noncoding RNAs may interact with the reprogramming factors to enhance reprogramming [25,45,59]. Bioinformatic analysis has been utilized to investigate iPS reprogramming not only at the level of gene expression and transcription factor binding but also at the epigenetic level.…”

Section: Bioinformatic Analysis Of Induced Pluripotencymentioning

confidence: 99%

Bioinformatic and Genomic Analyses of Cellular Reprogramming and Direct Lineage Conversion

Kareta

2016

Curr Pharmacol Rep

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Cellular reprogramming, whereby cell fate can be changed by the expression of a few defined factors, is a remarkable process that harnesses the innate ability of a cell's own genome to rework its expressional networks and function. Since cell lineages are defined by global regulation of gene expression, transcriptional regulators, and coupled to the epigenetic markings of the chromatin, changing the cell fate necessitates broad changes to these central cellular features. To properly characterize these changes, and the mechanisms that drive them, computational and genomic approaches are perfectly suited to provide a holistic picture of the reprogramming mechanisms. In particular, the use of bioinformatic analysis has been a major driver in the study of cellular reprogramming, as it relates to both induced pluripotency or direct lineage conversion. This review will summarize many of the bioinformatic studies that have advanced our knowledge of reprogramming and address future directions for these investigations.

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The primate-specific noncoding RNA HPAT5 regulates pluripotency during human preimplantation development and nuclear reprogramming

Cited by 153 publications

References 55 publications

The emerging molecular biology toolbox for the study of long noncoding RNA biology

The emerging molecular biology toolbox for the study of long noncoding RNA biology

Insights in human epigenomic dynamics through comparative primate analysis

Bioinformatic and Genomic Analyses of Cellular Reprogramming and Direct Lineage Conversion

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