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Article ; Online: CRISPR off-targets: a question of context.

Haeussler, Maximilian

2019 Volume 36, Issue 1, Page(s) 5–9

MeSH term(s)	Artifacts ; Base Pair Mismatch/genetics ; Base Pair Mismatch/physiology ; CRISPR-Cas Systems/genetics ; CRISPR-Cas Systems/physiology ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; Gene Editing/ethics ; Gene Editing/methods ; Gene Editing/trends ; Humans
Language	English
Publishing date	2019-11-16
Publishing country	Netherlands
Document type	Editorial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	48824-0
ISSN	1573-6822 ; 0742-2091
ISSN (online)	1573-6822
ISSN	0742-2091
DOI	10.1007/s10565-019-09497-1
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Article ; Online: CRISPOR: intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens.

Concordet, Jean-Paul / Haeussler, Maximilian

Nucleic acids research

2018 Volume 46, Issue W1, Page(s) W242–W245

Abstract: CRISPOR.org is a web tool for genome editing experiments with the CRISPR-Cas9 system. It finds guide RNAs in an input sequence and ranks them according to different scores that evaluate potential off-targets in the genome of interest and predict on- ... ...

Abstract	CRISPOR.org is a web tool for genome editing experiments with the CRISPR-Cas9 system. It finds guide RNAs in an input sequence and ranks them according to different scores that evaluate potential off-targets in the genome of interest and predict on-target activity. The list of genomes is continuously expanded, with more 150 genomes added in the last two years. CRISPOR tries to provide a comprehensive solution from selection, cloning and expression of guide RNA as well as providing primers needed for testing guide activity and potential off-targets. Recent developments include batch design for genome-wide CRISPR and saturation screens, creating custom oligonucleotides for guide cloning and the design of next generation sequencing primers to test for off-target mutations. CRISPOR is available from http://crispor.org, including the full source code of the website and a stand-alone, command-line version.
MeSH term(s)	Base Sequence ; CRISPR-Associated Protein 9 ; CRISPR-Cas Systems ; Gene Editing ; Gene Knockout Techniques ; Genome ; Internet ; Mutagenesis ; Oligonucleotides ; RNA/chemistry ; Software ; Workflow
Chemical Substances	Oligonucleotides ; RNA (63231-63-0) ; CRISPR-Associated Protein 9 (EC 3.1.-)
Language	English
Publishing date	2018-05-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gky354
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Article: A Meta-Atlas of the Developing Human Cortex Identifies Modules Driving Cell Subtype Specification.

Nano, Patricia R / Fazzari, Elisa / Azizad, Daria / Nguyen, Claudia V / Wang, Sean / Kan, Ryan L / Wick, Brittney / Haeussler, Maximilian / Bhaduri, Aparna

bioRxiv : the preprint server for biology

2023

Abstract: Human brain development requires the generation of hundreds of diverse cell types, a process targeted by recent single-cell transcriptomic profiling efforts. Through a meta-analysis of seven of these published datasets, we have generated 225 meta-modules ...

Abstract	Human brain development requires the generation of hundreds of diverse cell types, a process targeted by recent single-cell transcriptomic profiling efforts. Through a meta-analysis of seven of these published datasets, we have generated 225 meta-modules - gene co-expression networks that can describe mechanisms underlying cortical development. Several meta-modules have potential roles in both establishing and refining cortical cell type identities, and we validated their spatiotemporal expression in primary human cortical tissues. These include meta-module 20, associated with FEZF2+ deep layer neurons. Half of meta-module 20 genes are putative FEZF2 targets, including TSHZ3, a transcription factor associated with neurodevelopmental disorders. Human cortical organoid experiments validated that both factors are necessary for deep layer neuron specification. Importantly, subtle manipulations of these factors drive slight changes in meta-module activity that cascade into strong differences in cell fate - demonstrating how of our meta-atlas can engender further mechanistic analyses of cortical fate specification.
Language	English
Publishing date	2023-09-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.12.557406
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Article ; Online: Cholesteatoma Severely Impacts the Integrity and Bone Material Quality of the Incus.

Delsmann, Maximilian M / Bonik, Paul / Ocokoljic, Ana / Häussler, Sophia M / Püschel, Klaus / Praetorius, Mark / Amling, Michael / Peichl, Jonathan / Rolvien, Tim

Calcified tissue international

2023 Volume 113, Issue 6, Page(s) 609–617

Abstract: Cholesteatoma can lead to progressive destruction of the auditory ossicles along with conductive hearing loss but precise data on the microstructural, cellular, and compositional aspects of affected ossicles are not available. Here, we obtained incus ... ...

Abstract	Cholesteatoma can lead to progressive destruction of the auditory ossicles along with conductive hearing loss but precise data on the microstructural, cellular, and compositional aspects of affected ossicles are not available. Here, we obtained incus specimens from patients who had cholesteatoma with conductive hearing loss. Incudes were evaluated by micro-computed tomography, histomorphometry on undecalcified sections, quantitative backscattered electron imaging, and nanoindentation. Results were compared with two control groups taken from patients with chronic otitis media as well as from skeletally intact donors at autopsy. The porosity of incus specimens was higher in cholesteatoma than in chronic otitis media, along with a higher osteoclast surface per bone surface. Histomorphometric assessment revealed higher osteoid levels and osteocyte numbers in cholesteatoma incudes. Incudes affected by cholesteatoma also showed lower matrix mineralization compared with specimens from healthy controls and chronic otitis media. Furthermore, the modulus-to-hardness ratio was higher in cholesteatoma specimens compared with controls. Taken together, we demonstrated increased porosity along with increased osteoclast indices, impaired matrix mineralization, and altered biomechanical properties as distinct features of the incus in cholesteatoma. Based on our findings, a possible impact of impaired bone quality on conductive hearing loss should be further explored.
MeSH term(s)	Humans ; Incus ; Cholesteatoma, Middle Ear ; Hearing Loss, Conductive ; X-Ray Microtomography ; Otitis Media ; Chronic Disease
Language	English
Publishing date	2023-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	304266-2
ISSN	1432-0827 ; 0944-0747 ; 0008-0594 ; 0171-967X
ISSN (online)	1432-0827
ISSN	0944-0747 ; 0008-0594 ; 0171-967X
DOI	10.1007/s00223-023-01144-6
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Article: A Panoramic View of Cell Population Dynamics in Mammalian Aging.

Zhang, Zehao / Schaefer, Chloe / Jiang, Weirong / Lu, Ziyu / Lee, Jasper / Sziraki, Andras / Abdulraouf, Abdulraouf / Wick, Brittney / Haeussler, Maximilian / Li, Zhuoyan / Molla, Gesmira / Satija, Rahul / Zhou, Wei / Cao, Junyue

bioRxiv : the preprint server for biology

2024

Abstract: To elucidate the aging-associated cellular population dynamics throughout the body, here we present PanSci, a single-cell transcriptome atlas profiling over 20 million cells from 623 mouse tissue samples, encompassing a range of organs across different ... ...

Abstract	To elucidate the aging-associated cellular population dynamics throughout the body, here we present PanSci, a single-cell transcriptome atlas profiling over 20 million cells from 623 mouse tissue samples, encompassing a range of organs across different life stages, sexes, and genotypes. This comprehensive dataset allowed us to identify more than 3,000 unique cellular states and catalog over 200 distinct aging-associated cell populations experiencing significant depletion or expansion. Our panoramic analysis uncovered temporally structured, organ- and lineage-specific shifts of cellular dynamics during lifespan progression. Moreover, we investigated aging-associated alterations in immune cell populations, revealing both widespread shifts and organ-specific changes. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte-dependent. The breadth and depth of our 'cell-omics' methodology not only enhance our comprehension of cellular aging but also lay the groundwork for exploring the complex regulatory networks among varied cell types in the context of aging and aging-associated diseases.
Language	English
Publishing date	2024-03-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.01.583001
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Article ; Online: Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia.

Eze, Ugomma C / Bhaduri, Aparna / Haeussler, Maximilian / Nowakowski, Tomasz J / Kriegstein, Arnold R

Nature neuroscience

2021 Volume 24, Issue 4, Page(s) 584–594

Abstract: The human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single- ... ...

Abstract	The human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.
MeSH term(s)	Animals ; Cerebral Cortex/cytology ; Cerebral Cortex/embryology ; Ependymoglial Cells/cytology ; Humans ; Neural Stem Cells/cytology ; Neuroepithelial Cells/cytology ; Neurogenesis ; Single-Cell Analysis
Language	English
Publishing date	2021-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1420596-8
ISSN	1546-1726 ; 1097-6256
ISSN (online)	1546-1726
ISSN	1097-6256
DOI	10.1038/s41593-020-00794-1
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Article: Genome Editing with CRISPR-Cas9: Can It Get Any Better?

Haeussler, Maximilian / Concordet, Jean-Paul

Journal of genetics and genomics = Yi chuan xue bao

2016 Volume 43, Issue 5, Page(s) 239–250

Abstract: The CRISPR-Cas revolution is taking place in virtually all fields of life sciences. Harnessing DNA cleavage with the CRISPR-Cas9 system of Streptococcus pyogenes has proven to be extraordinarily simple and efficient, relying only on the design of a ... ...

Abstract	The CRISPR-Cas revolution is taking place in virtually all fields of life sciences. Harnessing DNA cleavage with the CRISPR-Cas9 system of Streptococcus pyogenes has proven to be extraordinarily simple and efficient, relying only on the design of a synthetic single guide RNA (sgRNA) and its co-expression with Cas9. Here, we review the progress in the design of sgRNA from the original dual RNA guide for S. pyogenes and Staphylococcus aureus Cas9 (SpCas9 and SaCas9). New assays for genome-wide identification of off-targets have provided important insights into the issue of cleavage specificity in vivo. At the same time, the on-target activity of thousands of guides has been determined. These data have led to numerous online tools that facilitate the selection of guide RNAs in target sequences. It appears that for most basic research applications, cleavage activity can be maximized and off-targets minimized by carefully choosing guide RNAs based on computational predictions. Moreover, recent studies of Cas proteins have further improved the flexibility and precision of the CRISPR-Cas toolkit for genome editing. Inspired by the crystal structure of the complex of sgRNA-SpCas9 bound to target DNA, several variants of SpCas9 have recently been engineered, either with novel protospacer adjacent motifs (PAMs) or with drastically reduced off-targets. Novel Cas9 and Cas9-like proteins called Cpf1 have also been characterized from other bacteria and will benefit from the insights obtained from SpCas9. Genome editing with CRISPR-Cas9 may also progress with better understanding and control of cellular DNA repair pathways activated after Cas9-induced DNA cleavage.
MeSH term(s)	Animals ; Base Sequence ; CRISPR-Cas Systems/genetics ; Gene Editing/methods ; Gene Knockout Techniques ; Genomics/methods ; Humans ; RNA, Guide, CRISPR-Cas Systems/genetics
Chemical Substances	RNA, Guide, CRISPR-Cas Systems
Language	English
Publishing date	2016-04-24
Publishing country	China
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2374568-X
ISSN	1873-5533 ; 1673-8527
ISSN (online)	1873-5533
ISSN	1673-8527
DOI	10.1016/j.jgg.2016.04.008
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Article: Genome Editing with CRISPR-Cas9: Can It Get Any Better?

Haeussler, Maximilian / Jean-Paul Concordet

Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China Journal of genetics and genomics. 2016 May 20, v. 43, no. 5

2016

Abstract	The CRISPR-Cas revolution is taking place in virtually all fields of life sciences. Harnessing DNA cleavage with the CRISPR-Cas9 system of Streptococcus pyogenes has proven to be extraordinarily simple and efficient, relying only on the design of a synthetic single guide RNA (sgRNA) and its co-expression with Cas9. Here, we review the progress in the design of sgRNA from the original dual RNA guide for S. pyogenes and Staphylococcus aureus Cas9 (SpCas9 and SaCas9). New assays for genome-wide identification of off-targets have provided important insights into the issue of cleavage specificity in vivo. At the same time, the on-target activity of thousands of guides has been determined. These data have led to numerous online tools that facilitate the selection of guide RNAs in target sequences. It appears that for most basic research applications, cleavage activity can be maximized and off-targets minimized by carefully choosing guide RNAs based on computational predictions. Moreover, recent studies of Cas proteins have further improved the flexibility and precision of the CRISPR-Cas toolkit for genome editing. Inspired by the crystal structure of the complex of sgRNA-SpCas9 bound to target DNA, several variants of SpCas9 have recently been engineered, either with novel protospacer adjacent motifs (PAMs) or with drastically reduced off-targets. Novel Cas9 and Cas9-like proteins called Cpf1 have also been characterized from other bacteria and will benefit from the insights obtained from SpCas9. Genome editing with CRISPR-Cas9 may also progress with better understanding and control of cellular DNA repair pathways activated after Cas9-induced DNA cleavage.
Keywords	bacteria ; computer software ; crystal structure ; DNA ; DNA damage ; DNA repair ; genome ; prediction ; proteins ; RNA ; Staphylococcus aureus ; Streptococcus pyogenes
Language	English
Dates of publication	2016-0520
Size	p. 239-250.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	2374568-X
ISSN	1873-5533 ; 1673-8527
ISSN (online)	1873-5533
ISSN	1673-8527
DOI	10.1016/j.jgg.2016.04.008
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Article: Single cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism.

Perez, Yonatan / Velmeshev, Dmitry / Wang, Li / White, Matthew / Siebert, Clara / Baltazar, Jennifer / Dutton, Natalia Garcia / Wang, Shaohui / Haeussler, Maximilian / Chamberlain, Stormy / Kriegstein, Arnold

bioRxiv : the preprint server for biology

2023

Abstract: Duplication 15q (dup15q) syndrome is the most common genetic cause of autism spectrum disorder (ASD). Due to a higher genetic and phenotypic homogeneity compared to idiopathic autism, dup15q syndrome provides a well-defined setting to investigate ASD ... ...

Abstract	Duplication 15q (dup15q) syndrome is the most common genetic cause of autism spectrum disorder (ASD). Due to a higher genetic and phenotypic homogeneity compared to idiopathic autism, dup15q syndrome provides a well-defined setting to investigate ASD mechanisms. Previous bulk gene expression studies identified shared molecular changes in ASD. However, how cell type specific changes compare across different autism subtypes and how they change during development is largely unknown. In this study, we used single cell and single nucleus mRNA sequencing of dup15q cortical organoids from patient iPSCs, as well as post-mortem patient brain samples. We find cell-type specific dysregulated programs that underlie dup15q pathogenesis, which we validate by spatial resolved transcriptomics using brain tissue samples. We find degraded identity and vulnerability of deep-layer neurons in fetal stage organoids and highlight increased molecular burden of postmortem upper-layer neurons implicated in synaptic signaling, a finding shared between idiopathic ASD and dup15q syndrome. Gene co-expression network analysis of organoid and postmortem excitatory neurons uncovers modules enriched with autism risk genes. Organoid developmental modules were involved in transcription regulation via chromatin remodeling, while postmortem modules were associated with synaptic transmission and plasticity. The findings reveal a shifting landscape of ASD cellular vulnerability during brain development.
Language	English
Publishing date	2023-09-22
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.22.559056
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Article ; Online: The dynseq browser track shows context-specific features at nucleotide resolution.

Nair, Surag / Barrett, Arjun / Li, Daofeng / Raney, Brian J / Lee, Brian T / Kerpedjiev, Peter / Ramalingam, Vivekanandan / Pampari, Anusri / Lekschas, Fritz / Wang, Ting / Haeussler, Maximilian / Kundaje, Anshul

Nature genetics

2022 Volume 54, Issue 11, Page(s) 1581–1583

MeSH term(s)	Nucleotides ; Software ; Databases, Genetic ; Internet ; Web Browser
Chemical Substances	Nucleotides
Language	English
Publishing date	2022-10-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-022-01194-w
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Zs.MG 46: Show issues

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