The N6-methyladenosine (m
A) modification is the most prevalent post-transcriptional mRNA modification, regulating mRNA decay and splicing. It plays a major role during normal development, ...differentiation, and disease progression. The modification is regulated by a set of writer, eraser, and reader proteins. The YTH domain family of proteins consists of three homologous m
A-binding proteins, Ythdf1, Ythdf2, and Ythdf3, which were suggested to have different cellular functions. However, their sequence similarity and their tendency to bind the same targets suggest that they may have overlapping roles. We systematically knocked out (KO) the Mettl3 writer, each of the Ythdf readers, and the three readers together (triple-KO). We then estimated the effect in vivo in mouse gametogenesis, postnatal viability, and in vitro in mouse embryonic stem cells (mESCs). In gametogenesis,
severity is increased as the deletion occurs earlier in the process, and Ythdf2 has a dominant role that cannot be compensated by Ythdf1 or Ythdf3, due to differences in readers' expression pattern across different cell types, both in quantity and in spatial location. Knocking out the three readers together and systematically testing viable offspring genotypes revealed a redundancy in the readers' role during early development that is
gene dosage-dependent. Finally, in mESCs there is compensation between the three Ythdf reader proteins, since the resistance to differentiate and the significant effect on mRNA decay occur only in the triple-KO cells and not in the single KOs. Thus, we suggest a new model for the Ythdf readers function, in which there is profound dosage-dependent redundancy when all three readers are equivalently coexpressed in the same cell types.
How the unique chromatin configuration of embryonic stem cells (ESCs) integrates inputs from exogenous stimuli to maintain pluripotency remains largely unknown. The ESC-specific ATP-dependent ...chromatin-remodelling (esBAF) complex maintains the accessibility of the target sites of Stat3, a leukaemia inhibitory factor (LIF) signalling effector, by preventing repressive localized polycomb-mediated trimethylation of Lys 27 of histone 3 (H3K27me3).
A functional and regulatory map of asthma Novershtern, Noa; Itzhaki, Zohar; Manor, Ohad ...
American journal of respiratory cell and molecular biology,
03/2008, Volume:
38, Issue:
3
Journal Article
Peer reviewed
Open access
The prevalence and morbidity of asthma, a chronic inflammatory airway disease, is increasing. Animal models provide a meaningful but limited view of the mechanisms of asthma in humans. A ...systems-level view of asthma that integrates multiple levels of molecular and functional information is needed. For this, we compiled a gene expression compendium from five publicly available mouse microarray datasets and a gene knowledge base of 4,305 gene annotation sets. Using this collection we generated a high-level map of the functional themes that characterize animal models of asthma, dominated by innate and adaptive immune response. We used Module Networks analysis to identify co-regulated gene modules. The resulting modules reflect four distinct responses to treatment, including early response, general induction, repression, and IL-13-dependent response. One module with a persistent induction in response to treatment is mainly composed of genes with suggested roles in asthma, suggesting a similar role for other module members. Analysis of IL-13-dependent response using protein interaction networks highlights a role for TGF-beta1 as a key regulator of asthma. Our analysis demonstrates the discovery potential of systems-level approaches and provides a framework for applying such approaches to asthma.
mRNA modification regulates pluripotency
When stem cells progress from an embryonic pluripotent state toward a particular lineage, molecular switches dismantle the transcription factor network that ...keeps the cell pluripotent. Geula
et al.
now show that N6-methyladenosine (m6A), a messenger RNA (mRNA) modification present on transcripts of pluripotency factors, drives this transition. Methylation destabilized mRNA transcripts and limited their translation efficiency, which promoted the timely decay of naïve pluripotency. This m6A methylation was also critical for mammalian development.
Science
, this issue p.
1002
A messenger RNA epigenetic modification regulates stem cell progression from the pluripotent to the differentiated state.
Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here, we identify Mettl3, an
N
6
-methyladenosine (m
6
A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout preimplantation epiblasts and naïve embryonic stem cells are depleted for m
6
A in mRNAs, yet are viable. However, they fail to adequately terminate their naïve state and, subsequently, undergo aberrant and restricted lineage priming at the postimplantation stage, which leads to early embryonic lethality. m
6
A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency-promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner.
Hereditary inclusion body myopathy (HIBM) is an adult onset, slowly progressive distal and proximal myopathy. Although the causing gene, GNE, encodes for a key enzyme in the biosynthesis of sialic ...acid, its primary function in HIBM remains unknown. To elucidate the pathological mechanisms leading from the mutated GNE to the HIBM phenotype, we attempted to identify and characterize early occurring downstream events by analyzing the genomic expression patterns of muscle specimens from 10 HIBM patients carrying the M712T Persian Jewish founder mutation and presenting mild histological changes, compared with 10 healthy matched control individuals, using GeneChip expression microarrays. When analyzing the expression profile data sets by the intersection of three statistic methods (Student’s t-test, TNoM and Info score), we found that the HIBM-specific transcriptome consists of 374 differentially expressed genes. The specificity of the HIBM transcriptome was assessed by the minimal transcript overlap found between HIBM and the transcriptome of nine additional muscle disorders including adult onset limb girdle myopathies, inflammatory myopathies and early onset conditions. A strikingly high proportion (18.6%) of the overall differentially expressed mRNAs of known function were found to encode for proteins implicated in various mitochondrial processes, revealing mitochondria pathways dysregulation. Mitochondrial morphological analysis by video-rate confocal microscopy showed a high degree of mitochondrial branching in cells of HIBM patients. The subtle involvement of mitochondrial processes identified in HIBM reveals an unexpected facet of HIBM pathophysiology which could at least partially explain the slow evolution of this disorder and give new insights in the disease mechanism.
Accurate segmentation of medical images is crucial for diagnostic purposes, including cell segmentation, tumor identification, and organ localization. Traditional convolutional neural network ...(CNN)-based approaches struggled to achieve precise segmentation results due to their limited receptive fields, particularly in cases involving multi-organ segmentation with varying shapes and sizes. The transformer-based approaches address this limitation by leveraging the global receptive field, but they often face challenges in capturing local information required for pixel-precise segmentation. In this work, we introduce DwinFormer, a hierarchical encoder-decoder architecture for medical image segmentation comprising a directional window (Dwin) attention and global self-attention (GSA) for feature encoding. The focus of our design is the introduction of Dwin block within DwinFormer that effectively captures local and global information along the horizontal, vertical, and depthwise directions of the input feature map by separately performing attention in each of these directional volumes. To this end, our Dwin block introduces a nested Dwin attention (NDA) that progressively increases the receptive field in horizontal, vertical, and depthwise directions and a convolutional Dwin attention (CDA) that captures local contextual information for the attention computation. While the proposed Dwin block captures local and global dependencies at the first two high-resolution stages of DwinFormer, the GSA block encodes global dependencies at the last two lower-resolution stages. Experiments over the challenging 3D Synapse Multi-organ dataset and Cell HMS dataset demonstrate the benefits of our DwinFormer over the state-of-the-art approaches. Our source code will be publicly available at \url{https://github.com/Daniyanaj/DWINFORMER}.
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