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200122 Hermanson SNPF Handouts 2020-01-29 How to control the size of the brain § An unexpectedly large number of genes associated with neuropsychology and psychiatric disease after recent investigations of cohorts is associated with brain development. epiGenetics – new insights into § What we learn from studying epigenetic mechanisms regulating neural stem cell characteristics neurodevelopmental disease (differentation, proliferation, death, autophagy, senescence, neurite outgrowth, axon pathfinding etc) assist us in developing new understanding for and Ola Hermanson, Karolinska Institutet, Stockholm, Sweden treatments of psychatric disease as well as neurodevelopmental, neurological and cancer disease. Ola Hermanson Ola Hermanson How to control the size of the brain The clinical picture – where is our focus § An unexpectedly large number of genes associated with neuropsychology and psychiatric disease after § Rubinstein-Taybi syndrome – mutations in the recent investigations of cohorts is associated with histone acetyl transferases CBP/p300 brain development. § What we learn from studying epigenetic mechanisms § Krabbe Disease – histone acetylation critical for regulating neural stem cell characteristics assists us in developing new understanding for and treatments oligodendrocyte differentiation and myelination of neuropsychology, psychiatric disease as well as neurodevelopmental, neurological, and neural § Rett Syndrome – mutations in the histone cancer disease. deacetylase-associated factor MeCP2. e.g., Epigenetics, 2013; Neurobiol Dis, 2014 Ola Hermanson Ola Hermanson Neurodegeneration - HD and cell death The clinical picture – where is our focus Childhood nervous system tumors – DIPG, medulloblastoma, neuroblastoma. Direct links to defects in histone modifying enzymes, for example mutations in histone demethylases (KDM6A/B). Molecules identified by us and our colleagues. e.g., Oncogene, 2008/2010; Nature, 2007/2013; Neuro-Oncology, 2014 e.g., Nature Neuroscience, 2015 Ola Hermanson Ola Hermanson 1 2020-01-29 Neurodegeneration - HD and cell death Stem cells respond to single factors – e.g., growth factors, hormones, vitamins etc e.g., Nature Neuroscience, 2015 Cell Research, 2007 Ola Hermanson Ola Hermanson Stem cells respond to single factors – Stem cells also respond to the microenvironment – e.g., growth factors, hormones, vitamins etc e.g., oxygen, substrate stiffness, roughness etc Cell Death Dis, 2010, 2015 Mol Cell Neurosci, 2011 PNAS, 2014 Cell Cycle, 2010 MRS Bull, 2010 PLoS One, 2010 J Biol Chem, 2009 Biomaterials, 2009 Mol Biol Cell, 2008 Biomaterials, 2007 Ola Hermanson Ola Hermanson Neural stem cells are very comfortable with substrates generated from On-going: printable spider silk substrates for iPS-derived neural stem cells – differentiation to functional cells – calcium imaging – improved light sheet recombinant spider silk proteins – 3D cultures and bioprinting microscopy allows whole-organ or tumor analysis Merged Calcein EthD Viability of SKN cells after FRESH bioprinting 100 *** * 24h 80 7d 7.5 psi 60 * 40 % live cells 20 24h 10 psi N/A 0 7.5 10 12.5 pressure [psi] Objects volume post printing 12.5psi **** **** 1.5 106 ] 3 m [ 1.0 106 10 psi 5.0 105 7d Object volume 0.0 12.5psi 10 psi; 8 mm/s 7d 10 psi; 8 mm/s 24h 12.5 psi; 8 mm/s 7d 12.5 psi; 8 mm/s 24h Bioprinting, 2019 Lewicki, on-going Biomaterials, 2012 BMC Biol, 2018 Ola Hermanson Ola Hermanson 2 2020-01-29 GlioStem: A new, polymer-based technology for detection of neural and glioblastoma progenitors – translation into clinic Submitted Ola Hermanson Ablation of a relatively general transcriptional repressor named NCoR is sufficient to induce differentiation into glia PLoS Biol, 2008 Nature, 2002 Cell, 2000 Ola Hermanson Ola Hermanson Removing specific histone modifying enzymes induces specific gene expression programs – inhibition of histone deacetylases Lithium and valproic acid/ergenyl share many features (mood disorders) (HDACs) – implications for autism (valproic acid/ergenyl) and – but NOT the HDACi ability multiple sclerosis (myelination) Cell Reports, 2014 Stem Cell Reports, 2014 J Mol Biol, 2014 From PharmWiki Ola Hermanson Ola Hermanson 3 2020-01-29 Lithium treatment show positive effects on late irradiation-induced Lithium treatment show positive effects on late irradiation-induced changes including cognition – but what are the mechanisms? changes including cognition – but what are the mechanisms? * Decreased DNA methylation on certain genes, e.g., Tppp and GAD65 * Late increases in levels of Tppp and GAD 65 Mol Psychiatry, 2020 Mol Psychiatry, 2020 Ola Hermanson Ola Hermanson Lithium treatment show positive effects on late irradiation-induced changes including cognition – * Tppp and GAD65 – current studies on human cells SMRT Ola Hermanson Ola Hermanson Neural stem cells without the co-repressor SMRT (similar to NCoR RAR/SMRT repress the expression of the histone demethylase but different gene) differentiate spontaneously into neurons – KDM6B/JMJD3 targeting lysine 27 (H3K27) – Novel treatments increased activity of retinoic acid receptor (RAR) now being developed based on targeting KDM6A and KDM6B Nature, 2007 Nature, 2007 Ola Hermanson Ola Hermanson 4 2020-01-29 The concept of ”poised” genes: (Tri)Methylation of H3K27 in a regulatory element = repression Acetylation of H3K27 and (Tri)Methylation of H3K4 in a regulatory element = activation Ola Hermanson Ola Hermanson We have thus found a way of removing the brake, methylation of H3K27. But how is the gas, methylation of H3K4, controlled? Ola Hermanson Ola Hermanson The transcription factor Pax6 is a master regulator of neural Pax6 can act as a repressor and progenitor/stem cells and preferentially binds to methylated DNA recruits H3K4me3 demethylase activity Gaudenzi et al, in revision Ola Hermanson Ola Hermanson 5 2020-01-29 The H3K4 demethylase KDM5C/SMCX co-occupy a cohort of The H3K4 demethylase KDM5C/SMCX co-occupy a cohort of genes with Pax6 in human neural progenitors, including Dll4 genes with Pax6 in human neural progenitors, including Dll4 Gaudenzi et al, in revision Gaudenzi et al, in revision Ola Hermanson Ola Hermanson § The HDAC-associated corepressor SMRT, regulated by retinoic acid, controls KDM6B/JMJD3 and KDM6A/UTX expression in neural progenitors and demethylates H3K27me3 on key genes § KDM5C/SMCX and Pax6 are major regulators of brain development genes including members of the NOTCH gene family such as Dll4 Ola Hermanson Ola Hermanson The transcription factor FOXP2 has been linked to the evolution of Q: If knockdown of NCoR in a progenitor/stem cell causes speech and language – interaction with NCOR? spontaneous glial differentiation and inhibits neuronal differentiation including neurite outgrowth and axon pathfinding – what role does NCoR play in neuronal differentiation? Hint: SMRT interacts with the transcription factor FoxP1 in heart development Ola Hermanson Ola Hermanson 6 2020-01-29 FOXP2 co-localizes with NCOR to genetic regions associated with Slitrks are transmembrane proteins associated with psychiatric speech and brain evolution – Genome wide studies (ChIP-Seq) in disorders such as Tourette syndrome and also brain evolution – human iPS cell-derived neural progenitors differences in neanderthals, denisovans, and homo sapiens Heldring, Gaudenzi et al, in preparation Ola Hermanson Ola Hermanson FOXP2 prefers to bind to NCOR before SMRT FOXP2 and NCOR are co-recruited to SLITRK genes NCOR knockdown results in increased expression of SLITRK genes Two gene regulatory elements revealed, GRE1 and GRE2 8 6 7 chr13 : 84,000,000 - 89,000,000 5 6 4 5 3 4 SLITRK Position 83, 877, 205 - 83, 332, 393 85, 792, 790 - 85, 799, 488 87, 672, 615 - 87, 696, 272 2 3 1 2 Genes SLITRK1 SLITRK6 SLITRK5 0 cluster 2 1 1 - Regulatory elements 0 -50kb -10kb +10kb +50kb -50kb -10kb +10kb +50kb -50kb -15kb +10kb +50kb D Ga l 4+ p cm v FOXP2+pCMVFOXP2+SMRTFOXP2+NCOR VP16+pM FOXP2+pM FOXP2+SMRTFOXP2+NCOR chr13 85,100 kb 85,150 kb chr13 87,730 kb Putative regulatory element Putative regulatory element FOXP2 10 FOXP2 10 0 0 10 NCOR 10 NCOR 0 0 Heldring, Gaudenzi et al, in preparation Heldring, Gaudenzi et al, in preparation Ola Hermanson Ola Hermanson 3C (chromosome conformation capture) reveals the 3D organization of the SLITRK gene landscape in human NSCs – A role for NCoR in controlling the factors implicated in the GRE1 – SLITRK1 and SLITRK6 : GRE2 – SLITRK5 evolution of the brain chr13 : 84,000,000 - 89,000,000 SLITRK Position 83, 877, 205 - 83, 332, 393 85, 792, 790 - 85, 799, 488 87, 672, 615 - 87, 696, 272 Genes SLITRK1 SLITRK6 SLITRK5 cluster 2 Regulatory elements 1 -50kb -10kb +10kb +50kb -50kb -10kb +10kb +50kb -50kb -15kb +10kb +50kb D Gene'regulatory'element'1' Gene'regulatory'element'2' 0.05" 0.09" 0.045" 0.08" 0.04" 0.07" 0.035" 0.06" 0.03" 0.05" 0.025" %input' %input' 0.04" 0.02" 0.03" 0.015" 0.02" 0.01" 0.01" 0.005" 0" 0" 50k" 9k"down" slitrk1" 9k"up" 50k"up" 50k" 10k" SLITRK6" 10k"up" 50k"up" 50k" 15k" SLITRK5" 10k"up" 50k"up" 50k"down" 9k"down" slitrk1" 9k"up" 50k"up" 50k"down"10k"down" SLITRK6" 10k"up" 50k"up" 50k"down"15k"down" SLITRK5" 10k"up" 50k"up" down" down" down" down" down" Heldring, Gaudenzi et al, in preparation Heldring, Gaudenzi et al, in preparation Ola Hermanson Ola Hermanson 7 2020-01-29 Speculation: NCOR seems to regulate genes that control neanderthal, denisovan, and human brain development GRE1 and GRE2 are HARs (human accelerated regions) – Katherine Pollard Ola Hermanson Ola Hermanson Thank you! § Giulia Gaudenzi § Bianca Migliori § Jakub Lewicki § Christina Neofytou § José María Oliva Montero § Vetenskapsrådet § Cancerfonden § Barncancerfonden § KI/SLL § Vinnova § MWLC § Klas Blomgren, Kristen Jepsen, Michael G. Rosenfeld, Julian Walfridsson, Anna Falk, Bertrand Joseph, Peter Nilsson, Per Uhlén, Anna Rising, Johan Holmberg et al § [email protected] Ola Hermanson 8.
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