Oliver J. Rando

University of Massachusetts Chan Medical School

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Nir Friedman

Hebrew University of Jerusalem

Fengyun Sun

University of Massachusetts Chan Medical School

Ana Bošković

European Molecular Biology Laboratory

Tsung-Han S. Hsieh

Howard Hughes Medical Institute

Nils Krietenstein

University of Massachusetts Chan Medical School

Thomas G. Fazzio

University of Massachusetts Chan Medical School

Colin C. Conine

Children's Hospital of Philadelphia

Vera D. Rinaldi

University of Massachusetts Chan Medical School

Upasna Sharma

National Bureau of Animal Genetic Resources

Stephen Buratowski

Harvard University

Cooperative Institutions

University of Massachusetts Chan Medical School

137

Harvard University

107

Howard Hughes Medical Institute

Massachusetts Institute of Technology

Centre National de la Recherche Scientifique

Broad Institute

Stanford University

Helmholtz Zentrum München

University of California, San Francisco

National Institutes of Health

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Phosphatidylinositol-dependE by the SWI/SNF-like BAF chr4 remodeling complex

Oliver J. Rando Keji Zhao Paul A. Janmey Gerald R. Crabtrec

Recently, several chromatin remodeling complexes in yeast, Drosophpe ila, and mammals have been shown to contain actin and actin-related wl proteins (arps). However, the function of actin in these complexes is ch unclear. Here, we show that the mammalian SWI/SNF-like BAF complex binds to phosphatidylinositol 4,5-bisphosphate (PIP2) micelles to and PIP2-containing mixed lipid vesicles, and that PIP2 binding allows co the complex to associate with actin pointed ends and branch points. st( Actin binds to at least two distinct domains in the C terminus of the W

Phosphatidylinositol 4,5-bisphosphate

SWI/SNF

Actin remodeling

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Chromatin 'programming' by sequence - is there more to the nucleosome code than %GC?

Journal of Biology (2009)

Amanda L. Hughes Oliver J. Rando

The role of genomic sequence in directing the packaging of eukaryotic genomes into chromatin has been the subject of considerable recent debate. A new paper from Tillo and Hughes shows that the intrinsic thermodynamic preference of a given sequence in the yeast genome for the histone octamer can largely be captured with a simple model, and in fact is mostly explained by %GC. Thus, the rules for predicting nucleosome occupancy from genomic sequence are much less complicated than has been claimed. See research article http://www.biomedcentral.com/1471-2105/10/442

Histone octamer

Sequence (biology)

10.1186/jbiol207

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Citations (43)

An integrated view of the structure and function of the human 4D nucleome

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Job Dekker Betul Akgol Oksuz Yang Zhang Ye Wang Miriam K. Minsk

Abstract The dynamic three-dimensional (3D) organization of the human genome (the “4D Nucleome”) is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales. The data reveal a rich complexity of chromatin domains and their sub-nuclear positions, and over one hundred thousand structural loops and promoter-enhancer interactions. We developed 3D models of population-based and individual cell-to-cell variation in genome structure, establishing connections between chromosome folding, nuclear organization, chromatin looping, gene transcription, and DNA replication. We demonstrate the use of computational methods to predict genome folding from DNA sequence, uncovering potential effects of genetic variants on genome structure and function. Together, this comprehensive analysis contributes insights into human genome organization and enhances our understanding of connections between the regulation of genome function and 3D genome organization in general.

10.1101/2024.09.17.613111

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Evidence for RNA or protein transport from somatic tissues to the male reproductive tract in mouse

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Vera D. Rinaldi Kathleen Messemer Kathleen Desevin Fengyun Sun Bethany C. Berry

ABSTRACT The development of tools to manipulate the mouse genome, including knockout and transgenic technology, revolutionized our ability to explore gene function in mammals. Moreover, for genes that are expressed in multiple tissues or at multiple stages of development, the use of tissue-specific expression of the Cre recombinase allows gene function to be perturbed in specific cell types and/or at specific times. However, it is well known that putative tissue-specific promoters often drive unanticipated “off target” expression. In our efforts to explore the biology of the male reproductive tract, we unexpectedly found that expression of Cre in the central nervous system resulted in recombination in the epididymis, a tissue where sperm mature for ~1-2 weeks following the completion of testicular development. Remarkably, we not only observed reporter expression in the epididymis when Cre expression was driven from neuron-specific transgenes, but also when Cre expression in the brain was induced from an AAV vector carrying a Cre expression construct. A surprisingly wide range of Cre drivers – including six different neuronal promoters as well as the adipose-specific AdipoQ Cre promoter – exhibited off target recombination in the epididymis, with a subset of drivers also exhibiting unexpected activity in other tissues such as the reproductive accessory glands. Finally, using a combination of parabiosis and serum transfer experiments, we find evidence supporting the hypothesis that Cre may be trafficked from its cell of origin to the epididymis through the circulatory system. Together, our findings should motivate extreme caution when interpreting conditional alleles, and suggest the exciting possibility of inter-tissue RNA or protein trafficking in modulation of reproductive biology.

Cre recombinase

Conditional gene knockout

10.1101/2022.02.08.479624

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Independent and complementary methods for large-scale structural analysis of mammalian chromatin

Genome Research (2007)

Jonathan H. Dennis Hua–Ying Fan Sheila M. Reynolds Guo‐Cheng Yuan James C. Meldrim

The fundamental building block of chromatin, the nucleosome, occupies 150 bp of DNA in a spaced arrangement that is a primary determinant in regulation of the genome. The nucleosomal organization of some regions of the human genome has been described, but mapping of these regions has been limited to a few kilobases. We have explored two independent and complementary methods for the high-throughput analysis of mammalian chromatin structure. Through adaptations to a protocol used to map yeast chromatin structure, we determined sites of nucleosomal protection over large regions of the mammalian genome using a tiling microarray. By modifying classical primer extension methods, we localized specific internucleosomally cleaved mammalian genomic sequences using a capillary electrophoresis sequencer in a manner that allows high-throughput nucleotide-resolution characterization of nucleosome protection patterns. We developed algorithms for the automated and unbiased analysis of the resulting data, a necessary step toward large-scale analysis. We validated these assays using the known positions of nucleosomes on the mouse mammary tumor virus LTR, and additionally, we characterized the previously unreported chromatin structure of the LCMT2 gene. These results demonstrate the effectiveness of the combined methods for reliable analysis of mammalian chromatin structure in a high-throughput manner.

ChIA-PET

ChIP-sequencing

ChIP-on-chip

10.1101/gr.5636607

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Feedback Control of Set1 Protein Levels Is Important for Proper H3K4 Methylation Patterns

Cell Reports (2014)

Luís Soares Marta Radman‐Livaja Sherry Lin Oliver J. Rando Stephen Buratowski

Methylation of histone H3 lysine 4 by the Set1 subunit of COMPASS correlates with active transcription. Here, we show that Set1 levels are regulated by protein degradation in response to multiple signals. Set1 levels are greatly reduced when COMPASS recruitment to genes, H3K4 methylation, or transcription is blocked. The degradation sequences map to N-terminal regions that overlap a previously identified autoinhibitory domain, as well as the catalytic domain. Truncation mutants of Set1 that cause under- or overexpression produce abnormal H3K4 methylation patterns on transcribed genes. Surprisingly, SAGA-dependent genes are more strongly affected than TFIID-dependent genes, reflecting differences in their chromatin dynamics. We propose that careful tuning of Set1 levels by regulated degradation is critical for the establishment and maintenance of proper H3K4 methylation patterns.

Histone Methylation

Transcription

10.1016/j.celrep.2014.02.017

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Citations (48)

Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal

Nature Communications (2015)

Rubing Zhao-Shea Steven R. DeGroot Liwang Liu Markus Vallaster Xue-Yan Pang

Increased anxiety is a prominent withdrawal symptom in abstinent smokers, yet the neuroanatomical and molecular bases underlying it are unclear. Here we show that withdrawal-induced anxiety increases activity of neurons in the interpeduncular intermediate (IPI), a subregion of the interpeduncular nucleus (IPN). IPI activation during nicotine withdrawal was mediated by increased corticotropin releasing factor (CRF) receptor-1 expression and signalling, which modulated glutamatergic input from the medial habenula (MHb). Pharmacological blockade of IPN CRF1 receptors or optogenetic silencing of MHb input reduced IPI activation and alleviated withdrawal-induced anxiety; whereas IPN CRF infusion in mice increased anxiety. We identified a mesointerpeduncular circuit, consisting of ventral tegmental area (VTA) dopaminergic neurons projecting to the IPN, as a potential source of CRF. Knockdown of CRF synthesis in the VTA prevented IPI activation and anxiety during nicotine withdrawal. These data indicate that increased CRF receptor signalling within a VTA–IPN–MHb circuit triggers anxiety during nicotine withdrawal. Abstinent smokers experience affective withdrawal symptoms that contribute to relapse, yet the circuitry and mechanisms underlying these symptoms are unknown. Here the authors identify a critical role for a ventral tegmental area-habenula-interpeduncular circuit in nicotine withdrawal-induced anxiety.

Interpeduncular nucleus

Habenula

Nicotine withdrawal

Pars compacta

10.1038/ncomms7770

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Citations (148)

Revisiting chromatin packaging in mouse sperm

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Qiangzong Yin Chih-Hsiang Yang Olga Strelkova Jingyi Wu Yu Sun

ABSTRACT Mammalian sperm exhibit an unusual and heavily-compacted genomic packaging state. In addition to its role in organizing the compact and hydrodynamic sperm head, it has been proposed that sperm chromatin architecture helps to program gene expression in the early embryo. Scores of genome-wide surveys in sperm have reported patterns of chromatin accessibility, histone localization, histone modification, and chromosome folding. Here, we revisit these studies in light of recent reports that sperm obtained from the mouse epididymis are contaminated with low levels of cell-free chromatin. In the absence of proper sperm lysis we readily recapitulate multiple prominent genome-wide surveys of sperm chromatin, suggesting that these profiles primarily reflect contaminating cell-free chromatin. Removal of cell-free DNA, along with appropriate lysis conditions, are required to reveal a sperm chromatin state distinct from most previous reports. Using ATAC-Seq to explore relatively accessible genomic loci, we identify a landscape of open loci associated with early development and transcriptional control. Histone modification and chromosome folding studies also strongly support the hypothesis that prior studies suffer from contamination, but technical challenges associated with reliably preserving the architecture of the compacted sperm head prevent us from confidently assaying true localization patterns for these epigenetic marks. Together, our studies strongly argue that our knowledge of mammalian chromosome packaging remains largely incomplete, and motivate future efforts to more accurately characterize genome organization in mature sperm.

Chromosome conformation capture

10.1101/2022.12.26.521943

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Citations (4)

Painting by Numbers: Increasing the Parts List for Chromatin Domains

Molecular Cell (2013)

Hsiuyi V. Chen Oliver J. Rando

ChIA-PET

10.1016/j.molcel.2013.02.007

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Genomic characterization reveals a simple histone H4 acetylation code

Proceedings of the National Academy of Sciences (2005)

Michael F. Dion Steven J. Altschuler Lani F. Wu Oliver J. Rando

The histone code hypothesis holds that covalent posttranslational modifications of histone tails are interpreted by the cell to yield a rich combinatorial transcriptional output. This hypothesis has been the subject of active debate in the literature. Here, we investigated the combinatorial complexity of the acetylation code at the four lysine residues of the histone H4 tail in budding yeast. We constructed yeast strains carrying all 15 possible combinations of mutations among lysines 5, 8, 12, and 16 to arginine in the histone H4 tail, mimicking positively charged, unacetylated lysine states, and characterized the resulting genome-wide changes in gene expression by using DNA microarrays. Only the lysine 16 mutation had specific transcriptional consequences independent of the mutational state of the other lysines (affecting ≈100 genes). In contrast, for lysines 5, 8, and 12, expression changes were due to nonspecific, cumulative effects seen as increased transcription correlating with an increase in the total number of mutations (affecting ≈1,200 genes). Thus, acetylation of histone H4 is interpreted by two mechanisms: a specific mechanism for lysine 16 and a nonspecific, cumulative mechanism for lysines 5, 8, and 12.

Histone H4

Histone code

Histone octamer

10.1073/pnas.0500136102

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Citations (389)