Sagiv Shifman
@sagivshifman.bsky.social
Professor @ Hebrew University | Neurodevelopmental disorders | Chromatin regulators in brain development and function
https://neurogenetics.huji.ac.il
https://neurogenetics.huji.ac.il
Pinned
CRISPR knockout screens reveal genes and pathways essential for neuronal differentiation and implicate PEDS1 in neurodevelopment - Nature Neuroscience
We conducted a CRISPR screen to identify genes essential for neural differentiation. By integrating these findings with mouse neuroanatomy, we demonstrated its utility in discovering a new PEDS1-relat...
www.nature.com
1/6 Thrilled to share our new paper in Nature Neuroscience with an amazing team of collaborators: CRISPR knockout screens map essential genes/pathways for neuronal differentiation and implicate PEDS1 in neurodevelopment. www.nature.com/articles/s41...
Reposted by Sagiv Shifman
3 papers in Cell @cellpress.bsky.social today exploring the mechanistic connection between Epstein-Barr virus and multiple sclerosis #MultipleSclerosis
cell.com/cell/fulltex...
cell.com/cell/fulltex...
www.cell.com/cell/fulltex...
cell.com/cell/fulltex...
cell.com/cell/fulltex...
www.cell.com/cell/fulltex...
January 13, 2026 at 4:25 PM
3 papers in Cell @cellpress.bsky.social today exploring the mechanistic connection between Epstein-Barr virus and multiple sclerosis #MultipleSclerosis
cell.com/cell/fulltex...
cell.com/cell/fulltex...
www.cell.com/cell/fulltex...
cell.com/cell/fulltex...
cell.com/cell/fulltex...
www.cell.com/cell/fulltex...
Reposted by Sagiv Shifman
Now final version out: Our manuscript connecting histone modifications with metabolism: How H4K16 acylations regulate inter +intranucleosomal interactions and confer resilience to metabolic challenges in vivo. Thanks to the team+ @sandrani.bsky.social
Enjoy 👇👇 www.cell.com/molecular-ce...
Enjoy 👇👇 www.cell.com/molecular-ce...
H4K16 acylations destabilize chromatin architecture and facilitate transcriptional response during metabolic perturbations
Nitsch et al. show that short-chain acylations of histone H4K16, acetylation (C2),
propionylation (C3), and butyrylation (C4) modulate chromatin structure in vitro.
These effects can translate in vivo...
www.cell.com
January 9, 2026 at 12:22 PM
Now final version out: Our manuscript connecting histone modifications with metabolism: How H4K16 acylations regulate inter +intranucleosomal interactions and confer resilience to metabolic challenges in vivo. Thanks to the team+ @sandrani.bsky.social
Enjoy 👇👇 www.cell.com/molecular-ce...
Enjoy 👇👇 www.cell.com/molecular-ce...
1/6 Thrilled to share our new paper in Nature Neuroscience with an amazing team of collaborators: CRISPR knockout screens map essential genes/pathways for neuronal differentiation and implicate PEDS1 in neurodevelopment. www.nature.com/articles/s41...
CRISPR knockout screens reveal genes and pathways essential for neuronal differentiation and implicate PEDS1 in neurodevelopment - Nature Neuroscience
We conducted a CRISPR screen to identify genes essential for neural differentiation. By integrating these findings with mouse neuroanatomy, we demonstrated its utility in discovering a new PEDS1-relat...
www.nature.com
January 5, 2026 at 3:14 PM
1/6 Thrilled to share our new paper in Nature Neuroscience with an amazing team of collaborators: CRISPR knockout screens map essential genes/pathways for neuronal differentiation and implicate PEDS1 in neurodevelopment. www.nature.com/articles/s41...
Reposted by Sagiv Shifman
While stories of singular DNA changes that drove evolution of human brain/behaviour remain seductive, advances across multiple fields of biology cast doubt on such simplistic narratives of our origins. A new paper from my lab shows how biobanks may speak to this fundamental question.🧪
Explainer🧵👇1/n
Explainer🧵👇1/n
Evaluating the effects of archaic protein-altering variants in living human adults
Promise and pitfalls of using large biobanks to study impacts of archaic protein-coding variants in living humans.
www.science.org
December 18, 2025 at 1:51 PM
While stories of singular DNA changes that drove evolution of human brain/behaviour remain seductive, advances across multiple fields of biology cast doubt on such simplistic narratives of our origins. A new paper from my lab shows how biobanks may speak to this fundamental question.🧪
Explainer🧵👇1/n
Explainer🧵👇1/n
Reposted by Sagiv Shifman
Our latest preprint revisits the classic model of mutation-selection balance.
Do human recessive genes fit Haldane's 100-year old model?
This work is by the wonderful @jonj-udd.bsky.social, and co-mentored by @jeffspence.github.io
www.biorxiv.org/content/10.6...
Do human recessive genes fit Haldane's 100-year old model?
This work is by the wonderful @jonj-udd.bsky.social, and co-mentored by @jeffspence.github.io
www.biorxiv.org/content/10.6...
Allele Frequencies at Recessive Disease Genes are Mainly Determined by Pleiotropic Effects in Heterozygotes
The classic theory of mutation-selection balance predicts the equilibrium frequency of genetic variation under negative selection. The model predicts a simple relationship between the total frequency ...
www.biorxiv.org
December 13, 2025 at 4:45 PM
Our latest preprint revisits the classic model of mutation-selection balance.
Do human recessive genes fit Haldane's 100-year old model?
This work is by the wonderful @jonj-udd.bsky.social, and co-mentored by @jeffspence.github.io
www.biorxiv.org/content/10.6...
Do human recessive genes fit Haldane's 100-year old model?
This work is by the wonderful @jonj-udd.bsky.social, and co-mentored by @jeffspence.github.io
www.biorxiv.org/content/10.6...
Reposted by Sagiv Shifman
“NOVA1 is a gene distinguishing modern humans from extinct hominids but evolutionary pressures that selected the modern allele remain elusive...Lead exposure on human brain organoids carrying the archaic NOVA1 variant disrupts FOXP2 expression, a gene crucial for human speech/language abilities.”🤔🧪
Impact of intermittent lead exposure on hominid brain evolution
Lead exposure, as influenced by NOVA1 expression, affected brain function in multiple hominid species.
www.science.org
October 16, 2025 at 3:46 PM
“NOVA1 is a gene distinguishing modern humans from extinct hominids but evolutionary pressures that selected the modern allele remain elusive...Lead exposure on human brain organoids carrying the archaic NOVA1 variant disrupts FOXP2 expression, a gene crucial for human speech/language abilities.”🤔🧪
Reposted by Sagiv Shifman
I wrote about gene-gene interactions (epistasis) and the implications for heritability, trait definitions, natural selection, and therapeutic interventions. Biology is clearly full of causal interactions, so why don't we see them in the data? A 🧵:
Beneath the surface of the sum
When genetic interactions matter and when they don't
open.substack.com
August 27, 2025 at 8:41 PM
I wrote about gene-gene interactions (epistasis) and the implications for heritability, trait definitions, natural selection, and therapeutic interventions. Biology is clearly full of causal interactions, so why don't we see them in the data? A 🧵:
Reposted by Sagiv Shifman
The two key studies of the International Brain Laboratory @intlbrainlab.bsky.social are out today!
A brain-wide map of neural activity during complex behaviour
www.nature.com/articles/s41...
Brain-wide representations of prior information in mouse decision-making
www.nature.com/articles/s41...
A brain-wide map of neural activity during complex behaviour
www.nature.com/articles/s41...
Brain-wide representations of prior information in mouse decision-making
www.nature.com/articles/s41...
A brain-wide map of neural activity during complex behaviour - Nature
The International Brain Laboratory presents a brain-wide electrophysiological map obtained from pooling data from 12 laboratories that performed the same standardized perceptual decision-making task i...
www.nature.com
September 3, 2025 at 3:46 PM
The two key studies of the International Brain Laboratory @intlbrainlab.bsky.social are out today!
A brain-wide map of neural activity during complex behaviour
www.nature.com/articles/s41...
Brain-wide representations of prior information in mouse decision-making
www.nature.com/articles/s41...
A brain-wide map of neural activity during complex behaviour
www.nature.com/articles/s41...
Brain-wide representations of prior information in mouse decision-making
www.nature.com/articles/s41...
Reposted by Sagiv Shifman
Extraordinary resource! "Comprehensive recordings from 621,733 neurons in 297 brain areas of 139 mice (12 labs) performing a decision-making task with sensory, motor & cognitive components: a public dataset to understand how computations distributed across & within brain areas drive behaviour."👇🧪
A brain-wide map of neural activity during complex behaviour - Nature
The International Brain Laboratory presents a brain-wide electrophysiological map obtained from pooling data from 12 laboratories that performed the same standardized perceptual decision-making task i...
www.nature.com
September 3, 2025 at 3:07 PM
Extraordinary resource! "Comprehensive recordings from 621,733 neurons in 297 brain areas of 139 mice (12 labs) performing a decision-making task with sensory, motor & cognitive components: a public dataset to understand how computations distributed across & within brain areas drive behaviour."👇🧪
Reposted by Sagiv Shifman
FOXP genes regulate Purkinje cell diversity and cerebellar morphogenesis
@nagham-farah.bsky.social
www.nature.com/articles/s41...
@nagham-farah.bsky.social
www.nature.com/articles/s41...
FOXP genes regulate Purkinje cell diversity and cerebellar morphogenesis - Nature Neuroscience
The Li lab mapped molecularly distinct Purkinje cell (PC) subtypes in 3D and linked them to adult cerebellar architecture. They found that Foxp1/Foxp2 are essential for PC diversity and that Foxp1+ PC...
www.nature.com
September 2, 2025 at 4:47 PM
FOXP genes regulate Purkinje cell diversity and cerebellar morphogenesis
@nagham-farah.bsky.social
www.nature.com/articles/s41...
@nagham-farah.bsky.social
www.nature.com/articles/s41...
Reposted by Sagiv Shifman
Fresh preprint by @flavia-con.bsky.social from our lab uncovers how SMCHD1 finds & binds chromatin using live-cell single-molecule imaging🔬
She reveals how SMCHD1 dynamically engages chromatin, including the inactive X chromosome, to maintain gene silencing.
www.biorxiv.org/content/10.1...
She reveals how SMCHD1 dynamically engages chromatin, including the inactive X chromosome, to maintain gene silencing.
www.biorxiv.org/content/10.1...
Selective interaction of the protein SMCHD1 with specific chromatin regions is governed by the loading factor LRIF1 and SMCHD1 ATPase activity
The chromosomal protein SMCHD1 is a GHKL ATPase that plays important roles in epigenetic silencing, including on the inactive X chromosome (Xi) and at the D4Z4 macrosatellite linked to regulation of D...
www.biorxiv.org
June 26, 2025 at 7:35 PM
Fresh preprint by @flavia-con.bsky.social from our lab uncovers how SMCHD1 finds & binds chromatin using live-cell single-molecule imaging🔬
She reveals how SMCHD1 dynamically engages chromatin, including the inactive X chromosome, to maintain gene silencing.
www.biorxiv.org/content/10.1...
She reveals how SMCHD1 dynamically engages chromatin, including the inactive X chromosome, to maintain gene silencing.
www.biorxiv.org/content/10.1...
Reposted by Sagiv Shifman
“Focus on single gene effects limits discovery and interpretation of
complex trait-associated variants” Very interesting preprint by Kathryn Lawrence @tamigj.bsky.social @sbmontgom.bsky.social
good arguments to move beyond single-gene-at-a-time approaches 🧪🧬
www.biorxiv.org/content/10.1...
complex trait-associated variants” Very interesting preprint by Kathryn Lawrence @tamigj.bsky.social @sbmontgom.bsky.social
good arguments to move beyond single-gene-at-a-time approaches 🧪🧬
www.biorxiv.org/content/10.1...
Focus on single gene effects limits discovery and interpretation of complex trait-associated variants
Standard QTL mapping approaches consider variant effects on a single gene at a time, despite abundant evidence for allelic pleiotropy, where a single variant can affect multiple genes simultaneously. ...
www.biorxiv.org
June 7, 2025 at 10:46 AM
“Focus on single gene effects limits discovery and interpretation of
complex trait-associated variants” Very interesting preprint by Kathryn Lawrence @tamigj.bsky.social @sbmontgom.bsky.social
good arguments to move beyond single-gene-at-a-time approaches 🧪🧬
www.biorxiv.org/content/10.1...
complex trait-associated variants” Very interesting preprint by Kathryn Lawrence @tamigj.bsky.social @sbmontgom.bsky.social
good arguments to move beyond single-gene-at-a-time approaches 🧪🧬
www.biorxiv.org/content/10.1...
Role of X chromosome and dosage-compensation mechanisms in complex trait genetics
www.cell.com/ajhg/fulltex...
www.cell.com/ajhg/fulltex...
Role of X chromosome and dosage-compensation mechanisms in complex trait genetics
We show that the X chromosome, understudied in genome-wide association studies, contributes
to complex traits in a manner shaped by dosage-compensation mechanisms. We find near-full
X inactivation bal...
www.cell.com
June 7, 2025 at 5:40 AM
Role of X chromosome and dosage-compensation mechanisms in complex trait genetics
www.cell.com/ajhg/fulltex...
www.cell.com/ajhg/fulltex...
Reposted by Sagiv Shifman
Delighted to have our work on Polygenic Modifiers of #TelomereBiologyDisorders, led by Michael Poeschla, @sashagusevposts.bsky.social, @mitchiela.bsky.social, @sharonsavage.bsky.social, @tummalalab.bsky.social, + co, published in @jclinical-invest.bsky.social today: www.jci.org/articles/vie...
June 4, 2025 at 1:59 AM
Delighted to have our work on Polygenic Modifiers of #TelomereBiologyDisorders, led by Michael Poeschla, @sashagusevposts.bsky.social, @mitchiela.bsky.social, @sharonsavage.bsky.social, @tummalalab.bsky.social, + co, published in @jclinical-invest.bsky.social today: www.jci.org/articles/vie...
Reposted by Sagiv Shifman
One of the coolest papers in the field of sex determination!
It is the first evidence that environmental aspects can affect mammalian sex determination!!
www.nature.com/articles/s41...
It is the first evidence that environmental aspects can affect mammalian sex determination!!
www.nature.com/articles/s41...
Maternal iron deficiency causes male-to-female sex reversal in mouse embryos - Nature
Iron-deficient conditions in pregnant mice can cause XY mouse embryos to develop female rather than male genitalia, revealing that iron metabolism has a role in determining male sex in mice.
www.nature.com
June 5, 2025 at 5:37 AM
One of the coolest papers in the field of sex determination!
It is the first evidence that environmental aspects can affect mammalian sex determination!!
www.nature.com/articles/s41...
It is the first evidence that environmental aspects can affect mammalian sex determination!!
www.nature.com/articles/s41...
Reposted by Sagiv Shifman
This seems to argue against the notion that girls are under-diagnosed because they express autistic symptoms differently, favoring a real sex difference in prevalence instead
There is an ongoing debate about phenotypic differences in #autism spectrum disorder between girls and boys. In this study, Pierce et al found no significant sex differences in ASD toddlers across 17 of 18 measures.
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Large-scale examination of early-age sex differences in neurotypical toddlers and those with autism spectrum disorder or other developmental conditions - Nature Human Behaviour
Autism spectrum disorder (ASD) is clinically heterogeneous, with ongoing debates about phenotypic differences between boys and girls. Leveraging the Get SET Early programme, Pierce and colleagues find...
www.nature.com
May 26, 2025 at 2:09 PM
This seems to argue against the notion that girls are under-diagnosed because they express autistic symptoms differently, favoring a real sex difference in prevalence instead
Reposted by Sagiv Shifman
There is an ongoing debate about phenotypic differences in #autism spectrum disorder between girls and boys. In this study, Pierce et al found no significant sex differences in ASD toddlers across 17 of 18 measures.
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Large-scale examination of early-age sex differences in neurotypical toddlers and those with autism spectrum disorder or other developmental conditions - Nature Human Behaviour
Autism spectrum disorder (ASD) is clinically heterogeneous, with ongoing debates about phenotypic differences between boys and girls. Leveraging the Get SET Early programme, Pierce and colleagues find...
www.nature.com
May 26, 2025 at 1:59 PM
There is an ongoing debate about phenotypic differences in #autism spectrum disorder between girls and boys. In this study, Pierce et al found no significant sex differences in ASD toddlers across 17 of 18 measures.
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Reposted by Sagiv Shifman
Sex-specific perturbations of neuronal development caused by mutations in the autism risk gene DDX3X
www.nature.com/articles/s41...
@natcomms.nature.com @derubeislab.bsky.social
www.nature.com/articles/s41...
@natcomms.nature.com @derubeislab.bsky.social
May 17, 2025 at 8:10 PM
Sex-specific perturbations of neuronal development caused by mutations in the autism risk gene DDX3X
www.nature.com/articles/s41...
@natcomms.nature.com @derubeislab.bsky.social
www.nature.com/articles/s41...
@natcomms.nature.com @derubeislab.bsky.social
Reposted by Sagiv Shifman
New publication!
We expand on our prior work demonstrating that pleiotropic effects of cognitive GWAS can provide biological insights into schizophrenia GWAS results. We differentiated "concordant" from "discordant" subsets of schizophrenia risk SNPs (1/3)
We expand on our prior work demonstrating that pleiotropic effects of cognitive GWAS can provide biological insights into schizophrenia GWAS results. We differentiated "concordant" from "discordant" subsets of schizophrenia risk SNPs (1/3)
May 14, 2025 at 2:13 PM
New publication!
We expand on our prior work demonstrating that pleiotropic effects of cognitive GWAS can provide biological insights into schizophrenia GWAS results. We differentiated "concordant" from "discordant" subsets of schizophrenia risk SNPs (1/3)
We expand on our prior work demonstrating that pleiotropic effects of cognitive GWAS can provide biological insights into schizophrenia GWAS results. We differentiated "concordant" from "discordant" subsets of schizophrenia risk SNPs (1/3)
Parent-of-origin regulation by maternal auts2 shapes neurodevelopment and behavior in fish
genomebiology.biomedcentral.com/articles/10....
genomebiology.biomedcentral.com/articles/10....
Parent-of-origin regulation by maternal auts2 shapes neurodevelopment and behavior in fish - Genome Biology
Background Parental experience can influence progeny behavior through gamete-mediated non-genetic inheritance, that is, mechanisms that do not involve changes in inherited DNA sequence. However, under...
genomebiology.biomedcentral.com
May 14, 2025 at 2:43 PM
Parent-of-origin regulation by maternal auts2 shapes neurodevelopment and behavior in fish
genomebiology.biomedcentral.com/articles/10....
genomebiology.biomedcentral.com/articles/10....
Scalable co-sequencing of RNA and DNA from individual nuclei www.nature.com/articles/s41...
Scalable co-sequencing of RNA and DNA from individual nuclei - Nature Methods
Building on a nucleosome-depletion strategy, DEFND-seq utilizes a droplet microfluidic platform to enable high-throughput co-profiling of DNA and RNA in single cells.
www.nature.com
May 13, 2025 at 5:48 PM
Scalable co-sequencing of RNA and DNA from individual nuclei www.nature.com/articles/s41...
Reposted by Sagiv Shifman
Delighted to share our latest work deciphering the landscape of chromatin accessibility and modeling the DNA sequence syntax rules underlying gene regulation during human fetal development! www.biorxiv.org/content/10.1... Read on for more: 🧵 1/16 #GeneReg 🧬🖥️
Dissecting regulatory syntax in human development with scalable multiomics and deep learning
Transcription factors (TFs) establish cell identity during development by binding regulatory DNA in a sequence-specific manner, often promoting local chromatin accessibility, and regulating gene expre...
www.biorxiv.org
May 3, 2025 at 6:27 PM
Delighted to share our latest work deciphering the landscape of chromatin accessibility and modeling the DNA sequence syntax rules underlying gene regulation during human fetal development! www.biorxiv.org/content/10.1... Read on for more: 🧵 1/16 #GeneReg 🧬🖥️
Reposted by Sagiv Shifman
Out today in AJHG, this work from my (recently graduated) student Teng Heng on recessive effects in 44k British South Asians from the Genes & Health project @genesandhealth.bsky.social . She found 185 independent hits of which >40% were novel. Worth looking for these in your own cohorts!
📣New from @hilarycmartin.bsky.social & co!
📄Widespread recessive effects on common diseases in a cohort of 44,000 British Pakistanis and Bangladeshis with high autozygosity
📄Widespread recessive effects on common diseases in a cohort of 44,000 British Pakistanis and Bangladeshis with high autozygosity
Widespread recessive effects on common diseases in a cohort of 44,000 British Pakistanis and Bangladeshis with high autozygosity
We leveraged the increased homozygosity in the Genes & Health cohort to perform recessive
association testing between 898 diseases and 10,045,406 whole-genome imputed variants,
as well as 607,981 whol...
www.cell.com
April 30, 2025 at 7:29 PM
Out today in AJHG, this work from my (recently graduated) student Teng Heng on recessive effects in 44k British South Asians from the Genes & Health project @genesandhealth.bsky.social . She found 185 independent hits of which >40% were novel. Worth looking for these in your own cohorts!
Reposted by Sagiv Shifman
Delighted to share the latest preprint from the lab led by Janith Seneviratne
We reveal novel roles for #embryonic regulators DPPA2/4 in facilitating a H2AK119Ub primed #chromatin state when aberrantly up-regulated in non-small cell lung #cancers 🧬🔬 (1/6)
www.biorxiv.org/content/10.1...
We reveal novel roles for #embryonic regulators DPPA2/4 in facilitating a H2AK119Ub primed #chromatin state when aberrantly up-regulated in non-small cell lung #cancers 🧬🔬 (1/6)
www.biorxiv.org/content/10.1...
April 28, 2025 at 11:07 AM
Delighted to share the latest preprint from the lab led by Janith Seneviratne
We reveal novel roles for #embryonic regulators DPPA2/4 in facilitating a H2AK119Ub primed #chromatin state when aberrantly up-regulated in non-small cell lung #cancers 🧬🔬 (1/6)
www.biorxiv.org/content/10.1...
We reveal novel roles for #embryonic regulators DPPA2/4 in facilitating a H2AK119Ub primed #chromatin state when aberrantly up-regulated in non-small cell lung #cancers 🧬🔬 (1/6)
www.biorxiv.org/content/10.1...
Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes - Nature Neuroscience
Sznajder et al. identified a molecular link between autism and myotonic dystrophy, showing that a tandem repeat mutation in a single gene can disrupt splicing of multiple autism-related genes during b...
www.nature.com
April 29, 2025 at 5:21 AM
Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes
www.nature.com/articles/s41...
www.nature.com/articles/s41...