Inferring the Sign of Kinase-Substrate Interactions by Combining Quantitative Phosphoproteomics with a Literature-Based Mammalian Kinome Network

Protein phosphorylation is a reversible post-translational modification commonly used by cell signaling networks to transmit information about the extracellular environment into intracellular organelles for the regulation of the activity and sorting of proteins within the cell. For this study we reconstructed a literature-based mammalian kinase-substrate network from several online resources. The interactions within this directed graph network connect kinases to their substrates, through specific phosphosites including kinase-kinase regulatory interactions. However, the "signs" of links, activation or inhibition of the substrate upon phosphorylation, within this network are mostly unknown. Here we show how we can infer the "signs" indirectly using data from quantitative phosphoproteomics experiments applied to mammalian cells combined with the literature-based kinase-substrate network. Our inference method was able to predict the sign for 321 links and 153 phosphosites on 120 kinases, resulting in signed and directed subnetwork of mammalian kinase-kinase interactions. Such an approach can rapidly advance the reconstruction of cell signaling pathways and networks regulating mammalian cells.Comment: 5 page, 3 figures, IEEE-BIBE confrenc

Epigenetic control of oligodendrocyte development:adding new players to old keepers

International audienceEmerging and strengthening evidence suggests an importantrole of myelin in plasticity and axonal survival. However, themechanisms regulating progression from oligodendrocyteprogenitor cells (OPCs) to myelinating oligodendrocytes remainonly partially understood. A series of overlapping yet distinctepigenetic events occur as a proliferating OPC exits the cellcycle, initiates differentiation, and becomes a myelin-formingoligodendrocyte that wraps axons. Here we discuss recentadvances towards understanding the epigenetic control ofoligodendrocyte development that integrates environmentalstimuli. We suggest that OPCs are directly responsive toextrinsic signals due to predominantly euchromatic nuclei,while the heterochromatic nuclei render differentiating andmyelinating cells less susceptible to signals modulating theepigenome

Complementing computationally predicted regulatory sites in Tractor_DB using a pattern matching approach.

Prokaryotic genomes annotation has focused on genes location and function. The lack of regulatory information has limited the knowledge on cellular transcriptional regulatory networks. However, as more phylogenetically close genomes are sequenced and annotated, the implementation of phylogenetic footprinting strategies for the recognition of regulators and their regulons becomes more important. In this paper we describe a comparative genomics approach to the prediction of new gamma-proteobacterial regulon members. We take advantage of the phylogenetic proximity of Escherichia coli and other 16 organisms of this subdivision and the intensive search of the space sequence provided by a pattern-matching strategy. Using this approach we complement predictions of regulatory sites made using statistical models currently stored in Tractor_DB, and increase the number of transcriptional regulators with predicted binding sites up to 86. All these computational predictions may be reached at Tractor_DB (www.bioinfo.cu/Tractor_DB, www.tractor.lncc.br, www.ccg.unam.mx/Computational_Genomics/tractorDB/). We also take a first step in this paper towards the assessment of the conservation of the architecture of the regulatory network in the gamma-proteobacteria through evaluating the conservation of the overall connectivity of the network

Mechanostimulation Promotes Nuclear and Epigenetic Changes in Oligodendrocytes

Oligodendrocyte progenitors respond to biophysical or mechanical signals, and it has been reported that mechanostimulation modulates cell proliferation, migration, and differentiation. Here we report the effect of three mechanical stimuli on mouse oligodendrocyte progenitor differentiation and identify the molecular components of the linker of nucleoskeleton and cytoskeleton (LINC) complex (i.e., SYNE1) as transducers of mechanical signals to the nucleus, where they modulate the deposition of repressive histone marks and heterochromatin formation. The expression levels of LINC components increased during progenitor differentiation and silencing the Syne1 gene resulted in aberrant histone marks deposition, chromatin reorganization and impaired myelination. We conclude that spatial constraints, via the actin cytoskeleton and LINC complex, mediate nuclear changes in oligodendrocyte progenitors that favor a default pathway of differentiation. Significance statement: It is recognized that oligodendrocyte progenitors are mechanosensitive cells. However, the molecular mechanisms translating mechanical stimuli into oligodendrocyte differentiation remain elusive. This study identifies components of the mechanotransduction pathway in the oligodendrocyte lineage

Epigenetic control of oligodendrocyte development: adding new players to old keepers

Emerging and strengthening evidence suggests an important role of myelin in plasticity and axonal survival. However, the mechanisms regulating progression from oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes remain only partially understood. A series of overlapping yet distinct epigenetic events occur as a proliferating OPC exits the cell cycle, initiates differentiation, and becomes a myelin-forming oligodendrocyte that wraps axons. Here we discuss recent advances towards understanding the epigenetic control of oligodendrocyte development that integrates environmental stimuli. We suggest that OPCs are directly responsive to extrinsic signals due to predominantly euchromatic nuclei, while the heterochromatic nuclei render differentiating and myelinating cells less susceptible to signals modulating the epigenome

The stability of the myelinating oligodendrocyte transcriptome is regulated by the nuclear lamina

Summary: Oligodendrocytes are specialized cells that insulate and support axons with their myelin membrane, allowing proper brain function. Here, we identify lamin A/C (LMNA/C) as essential for transcriptional and functional stability of myelinating oligodendrocytes. We show that LMNA/C levels increase with differentiation of progenitors and that loss of Lmna in differentiated oligodendrocytes profoundly alters their chromatin accessibility and transcriptional signature. Lmna deletion in myelinating glia is compatible with normal developmental myelination. However, altered chromatin accessibility is detected in fully differentiated oligodendrocytes together with increased expression of progenitor genes and decreased levels of lipid-related transcription factors and inner mitochondrial membrane transcripts. These changes are accompanied by altered brain metabolism, lower levels of myelin-related lipids, and altered mitochondrial structure in oligodendrocytes, thereby resulting in myelin thinning and the development of a progressively worsening motor phenotype. Overall, our data identify LMNA/C as essential for maintaining the transcriptional and functional stability of myelinating oligodendrocytes