Using brain cell-type-specific protein interactomes to interpret genetic data in schizophrenia

AbstractGenetics have nominated many schizophrenia risk genes that lack functional interpretation. To empower such interpretation, we executed interaction proteomics for six risk genes in human induced neurons and found the resulting protein network to be enriched for common variant risk of schizophrenia in Europeans and East Asians. The network is down-regulated in layer 5/6 cortical neurons of patients and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and also contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in patients with schizophrenia and bipolar disease. Our findings establish brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and psychiatric diseases.One Sentence SummaryNeuronal protein interactomes is an organizing framework for integrating genetic and transcriptomic data in schizophrenia.

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Interaction studies of risk proteins in human induced neurons reveal convergent biology and novel mechanisms underlying autism spectrum disorders

10.1101/2021.10.07.21264575 ◽

2021 ◽

Author(s):

Greta Pintacuda ◽

Yu-Han H Hsu ◽

Kalliopi Tsafou ◽

Ka Wan Li ◽

Jacqueline M Martin ◽

...

Keyword(s):

Autism Spectrum Disorders ◽

Rare Variant ◽

Specific Interaction ◽

Autism Spectrum ◽

Brain Cell ◽

Synaptic Proteins ◽

Cell Type ◽

Risk Genes ◽

Cell Type Specific ◽

Spectrum Disorders

Sequencing studies of autism spectrum disorders (ASDs) have identified numerous risk genes with enriched expression in the human brain, but it is still unclear how these genes converge into cell type-specific networks and how their encoded proteins mechanistically contribute to ASDs. To address this question, we performed brain cell type-specific interaction proteomics to build a protein-protein interaction network for 13 ASD risk genes in human excitatory neurons derived from iPS cells. The network contains many (>90%) reproducible interactions not reported in the literature and is enriched for transcriptionally perturbed genes observed in layer 2/3 cortical neurons of ASD patients, indicating that it can be explored for ASD-relevant biological discovery. We leveraged the network dataset to show that the brain-specific isoform of ANK2 is important for its interactions with synaptic proteins and characterized a PTEN-AKAP8L interaction that influences neuronal growth through the mTOR pathway. The IGF2BP1-3 complex emerges as a point of convergence in the network, and we showed that this complex is involved in a transcriptional circuit concentrating both common and rare variant risk of ASDs. Finally, we found the network itself enriched for ASD rare variant risk, indicating that it can complement genetic datasets for prioritizing additional risk genes. Our findings establish brain cell type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in ASDs and illustrate how both individual and convergent interactions lead to biological insights into the disease.

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Brain cell type–specific enhancer–promoter interactome maps and disease-risk association

Science ◽

10.1126/science.aay0793 ◽

2019 ◽

Vol 366 (6469) ◽

pp. 1134-1139 ◽

Cited By ~ 91

Author(s):

Alexi Nott ◽

Inge R. Holtman ◽

Nicole G. Coufal ◽

Johannes C. M. Schlachetzki ◽

Miao Yu ◽

...

Keyword(s):

Genetic Variation ◽

Disease Risk ◽

Phenotypic Diversity ◽

Cell Types ◽

Brain Cell ◽

Brain Diseases ◽

Cell Type ◽

Functional Interpretation ◽

Risk Variants ◽

Cell Type Specific

Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer’s disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type–specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.

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Faculty Opinions recommendation of LIM factor Lhx3 contributes to the specification of motor neuron and interneuron identity through cell-type-specific protein-protein interactions.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1008881.114208 ◽

2002 ◽

Author(s):

Judith S Eisen

Keyword(s):

Motor Neuron ◽

Protein Interactions ◽

Specific Protein ◽

Cell Type ◽

Protein Protein Interactions ◽

Cell Type Specific

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Generating Cell Type-Specific Protein Signatures from Non-symptomatic and Diseased Tissues

Annals of Biomedical Engineering ◽

10.1007/s10439-020-02507-y ◽

2020 ◽

Vol 48 (8) ◽

pp. 2218-2232

Author(s):

Jessica S. Sadick ◽

Lorin A. Crawford ◽

Harry C. Cramer ◽

Christian Franck ◽

Shane A. Liddelow ◽

...

Keyword(s):

Specific Protein ◽

Cell Type ◽

Protein Signatures ◽

Cell Type Specific

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Differential pial and penetrating arterial responses examined by optogenetic activation of astrocytes and neurons

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211010355 ◽

2021 ◽

pp. 0271678X2110103

Author(s):

Nao Hatakeyama ◽

Miyuki Unekawa ◽

Juri Murata ◽

Yutaka Tomita ◽

Norihiro Suzuki ◽

...

Keyword(s):

Cortical Neurons ◽

Acetylcholine Receptors ◽

Step Function ◽

Muscarinic Acetylcholine Receptors ◽

Cell Type ◽

Function Type ◽

Neuron Activation ◽

Cell Type Specific ◽

Arterial Responses

A variety of brain cells participates in neurovascular coupling by transmitting and modulating vasoactive signals. The present study aimed to probe cell type-dependent cerebrovascular (i.e., pial and penetrating arterial) responses with optogenetics in the cortex of anesthetized mice. Two lines of the transgenic mice expressing a step function type of light-gated cation channel (channelrhodopsine-2; ChR2) in either cortical neurons (muscarinic acetylcholine receptors) or astrocytes (Mlc1-positive) were used in the experiments. Photo-activation of ChR2-expressing astrocytes resulted in a widespread increase in cerebral blood flow (CBF), extending to the nonstimulated periphery. In contrast, photo-activation of ChR2-expressing neurons led to a relatively localized increase in CBF. The differences in the spatial extent of the CBF responses are potentially explained by differences in the involvement of the vascular compartments. In vivo imaging of the cerebrovascular responses revealed that ChR2-expressing astrocyte activation led to the dilation of both pial and penetrating arteries, whereas ChR2-expressing neuron activation predominantly caused dilation of the penetrating arterioles. Pharmacological studies showed that cell type-specific signaling mechanisms participate in the optogenetically induced cerebrovascular responses. In conclusion, pial and penetrating arterial vasodilation were differentially evoked by ChR2-expressing astrocytes and neurons.

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Btbd11 is an inhibitory interneuron specific synaptic scaffolding protein that supports excitatory synapse structure and function

10.1101/2021.11.01.466782 ◽

2021 ◽

Author(s):

Alexei M. Bygrave ◽

Ayesha Sengupta ◽

Ella P. Jackert ◽

Mehroz Ahmed ◽

Beloved Adenuga ◽

...

Keyword(s):

Inhibitory Interneuron ◽

Nmda Receptor Antagonist ◽

Specific Protein ◽

Network Activity ◽

Scaffolding Protein ◽

Inhibitory Interneurons ◽

Cell Type ◽

Cell Type Specific

Synapses in the brain exhibit cell–type–specific differences in basal synaptic transmission and plasticity. Here, we evaluated cell–type–specific differences in the composition of glutamatergic synapses, identifying Btbd11, as an inhibitory interneuron–specific synapse–enriched protein. Btbd11 is highly conserved across species and binds to core postsynaptic proteins including Psd–95. Intriguingly, we show that Btbd11 can undergo liquid–liquid phase separation when expressed with Psd–95, supporting the idea that the glutamatergic post synaptic density in synapses in inhibitory and excitatory neurons exist in a phase separated state. Knockout of Btbd11 from inhibitory interneurons decreased glutamatergic signaling onto parvalbumin–positive interneurons. Further, both in vitro and in vivo, we find that Btbd11 knockout disrupts network activity. At the behavioral level, Btbd11 knockout from interneurons sensitizes mice to pharmacologically induced hyperactivity following NMDA receptor antagonist challenge. Our findings identify a cell–type–specific protein that supports glutamatergic synapse function in inhibitory interneurons–with implication for circuit function and animal behavior.

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Transcribed enhancers in the human brain identify novel disease risk mechanisms

10.1101/2021.05.14.443421 ◽

2021 ◽

Author(s):

Pengfei Dong ◽

Gabriel E. Hoffman ◽

Pasha Apontes ◽

Jaroslav Bendl ◽

Samir Rahman ◽

...

Keyword(s):

Human Brain ◽

Disease Risk ◽

Association Studies ◽

Population Level ◽

Cell Type ◽

Level Variation ◽

Functional Interpretation ◽

Neuropsychiatric Diseases ◽

Order Of Magnitude ◽

Cell Type Specific

Enhancer RNAs (eRNAs) constitute an important tissue- and cell-type-specific layer of the regulome. Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding the population-level variation of eRNAs in the human brain. We jointly analyzed cell type-specific transcriptome and regulome data to identify 30,795 neuronal and 23,265 non-neuronal eRNAs, expanding the catalog of known human brain eRNAs by an order of magnitude. Examination of the population-level variation of the transcriptome and regulome in 1,382 brain samples identified reproducible changes affecting cis- and trans-co-regulation of eRNA-gene modules in schizophrenia. We show that 13% of schizophrenia heritability is jointly mediated in cis by brain gene and eRNA expression. Inclusion of eRNAs in transcriptome-wide association studies facilitated fine-mapping and functional interpretation of disease loci. Overall, our study characterizes the eRNA-gene regulome and genetic mechanisms in the human cortex in both healthy and disease states.

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Cell Type-Specific Role of RNA Nuclease SMG6 in Neurogenesis

Cells ◽

10.3390/cells10123365 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3365

Author(s):

Gabriela Maria Guerra ◽

Doreen May ◽

Torsten Kroll ◽

Philipp Koch ◽

Marco Groth ◽

...

Keyword(s):

Stem Cells ◽

Cell Fate ◽

Cortical Neurons ◽

Embryonic Stem ◽

Normal Structure ◽

Mutant Mice ◽

Cell Type ◽

Nonsense Mediated Mrna Decay ◽

A Cell ◽

Cell Type Specific

SMG6 is an endonuclease, which cleaves mRNAs during nonsense-mediated mRNA decay (NMD), thereby regulating gene expression and controling mRNA quality. SMG6 has been shown as a differentiation license factor of totipotent embryonic stem cells. To investigate whether it controls the differentiation of lineage-specific pluripotent progenitor cells, we inactivated Smg6 in murine embryonic neural stem cells. Nestin-Cre-mediated deletion of Smg6 in mouse neuroprogenitor cells (NPCs) caused perinatal lethality. Mutant mice brains showed normal structure at E14.5 but great reduction of the cortical NPCs and late-born cortical neurons during later stages of neurogenesis (i.e., E18.5). Smg6 inactivation led to dramatic cell death in ganglionic eminence (GE) and a reduction of interneurons at E14.5. Interestingly, neurosphere assays showed self-renewal defects specifically in interneuron progenitors but not in cortical NPCs. RT-qPCR analysis revealed that the interneuron differentiation regulators Dlx1 and Dlx2 were reduced after Smg6 deletion. Intriguingly, when Smg6 was deleted specifically in cortical and hippocampal progenitors, the mutant mice were viable and showed normal size and architecture of the cortex at E18.5. Thus, SMG6 regulates cell fate in a cell type-specific manner and is more important for neuroprogenitors originating from the GE than for progenitors from the cortex.

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