Jan 9 2023

in memoriam

"Every amino acid matters, but people matter more" - the work of C. David Allis rewrote the textbook on how gene expression is regulated, but to everyone lucky to have known him personally, his impact extended far beyond fundamental discoveries. Dave's optimism and infectious excitement for science paired uniquely with a humble and gentle personality. Seemingly random souvenirs and photos of family and lab members past and present (the "lab family" term was used often) covered his office floor to ceiling, and brought more joy to him than his (well deserved) Nike of Samothrace. Colors of chromatin shine less brightly today, but his legacy will live on.

Nov 1 2022

New Lab Member:

Cameron joins the lab! It takes special courage to be the first employee - when scientific challenges are overshadowed by organizational ones. Welcome!

Oct 24 2022

New Paper:

A fantastic story by Yadira Soto-Feliciano, Francisco Sanchez-Rivera, and many great collaborators in the Allis, Lowe and Armstrong labs is finally out in Cancer Discovery! One step closer to understanding the (non)redundancies of Mixed Lineage Leukemia methyltransferases, and how they can be leveraged in practical therapies for AML. Congratulations to Yadira and all!

Oct 12 2022

New Project:

As part of Interstellar Initiative, we have teamed up with Ankur Jain (Whitehead/MIT) and Noritaka Adachi (Tokyo Medical and Dental University) to study chromatin defects in Snyder-Robinson syndrome. Stay tuned for an update in a few months!

Research

All* cells in human body carry same "blueprint" of genomic DNA, yet their phenotypes and functions are remarkably different - suggesting that genes are differentially regulated.

*exclusions apply, as always

Moreover, ~3.2 billion base pairs of DNA in every human cell* are folded into a nucleus - usually only a few microns in diameter - while preserving precise regulation of individual gene function. We aim to understand how this extraordinary level of compaction is achieved, and how, when misregulated, it drives human disease - from malignancy to developmental disorders.

We study gene regulation by H1 linker histones - small, dynamic proteins that contribute to both compaction of chromatin fiber (a complex of DNA and many nuclear proteins), and regulation of gene expression.

People

Alexey A. Soshnev

PI

Cameron Chapa

research associate

positions available!..

(...and your face could be here!)

Publications

at UTSA:

  1. Soto-Feliciano YM, Sanchez-Rivera FJ, Perner F, Barrows DW, Kastenhuber ER, Ho Y-J, Carroll TS, Xiong Y, Anand D, Soshnev AA, Gates L, Beytagh MC, Cheon D, Gu CS, Liu XS, Krivtsov AV, Meneses M, de Stanchina E, Stone RM, Armstrong SA, Lowe SW, Allis CD. A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition. Cancer Disc, Oct 20 2022, https://doi.org/10.1158/2159-8290.CD-22-0416


Postdoctoral:

  1. Soshnev AA*, Allis CD, Cesarman E, Melnick AM*. Histone H1 mutations in lymphoma: a link(er) between chromatin organization, developmental reprogramming, and cancer. Cancer Res. 2021 Dec 15;81(24):6061-6070. PMID: 34580064 (*, corresponding author)

  2. Yusufova N, Kloetgen A, Teater M, Osunsade A, Camarillo JM, Chin CR, Doane A, Venters BJ, Portillo-Ledesma S, Conway J, Philips J, Elemento O, Scott DW, Beguelin W, Licht JD, Kelleher N, Staudt LM, Skoultchi AI, Keogh MC, Apostolou E, Mason C, Imielinski M, Schlick T, David Y, Tsirigos A, Allis CD, Soshnev AA*, Cesarman E*, Melnick AM.* Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture. Nature. 2021 Jan 14; 589(7841):299-305 PMID: 33299181 (*, corresponding author) - highlighted in Nature Reviews Genetics; highlighted in Cancer Discovery; recommended by F1000.

  3. Phillips RE, Soshnev AA, Allis CD. Epigenomic Reprogramming as a Driver of Malignant Glioma. Cancer Cell. 2020 Nov 9;38(5):647-660. PMID: 32916125

  4. Béguelin W, Teater M, Meydan C, Hoehn KB, Phillip JM, Soshnev AA, Venturutti L, Rivas MA, Calvo-Fernández MT, Gutierrez J, Camarillo JM, Takata K, Tarte K, Kelleher NL, Steidl C, Mason CE, Elemento O, Allis CD, Kleinstein SH, Melnick AM. Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response. Cancer Cell. 2020 May 11; 37(5):655-673.e11. PMID: 32396861

  5. Nacev BA, Feng L, Bagert JD, Lemiesz AE, Gao J, Soshnev AA, Kundra R, Schultz N, Muir TW, Allis CD. The expanding landscape of 'oncohistone' mutations in human cancers. Nature. 2019 Mar; 567(7749):473-478. PMID: 30894748.

  6. Burdin DV, Kolobov AA, Brocker C, Soshnev AA, Samusik N, Demyanov AV, Brilloff S, Jarzebska N, Martens-Lobenhoffer J, Mieth M, Maas R, Bornstein SR, Bode-Boger SM, Gonzalez F, Weiss N, Rodionov RN. Diabetes-linked transcription factor HNF4α regulates metabolism of endogenous methylarginines and β-aminoisobutyric acid by controlling expression of alanine-glyoxylate aminotransferase 2. Sci Rep. 2016 Oct 18; 6:35503. PMID: 27752141

  7. Soshnev AA*, Josefowicz SJ, Allis CD*. Greater than the sum of parts: the complexity of dynamic epigenome. Mol Cell. 2016 Jun 2;62(5):681-94. PMID: 27259201 (*, corresponding author).

  8. Maze I, Wenderski W, Noh KM, Bagot RC, Tzavaras N, Purushothaman I, Elsässer SJ, Guo Y, Ionete C, Hurd YL, Tamminga CA, Halene T, Farrelly L, Soshnev AA, Wen D, Rafii S, Birtwistle MR, Akbarian S, Buchholz BA, Blitzer RD, Nestler EJ, Yuan ZF, Garcia BA, Shen L, Molina H, Allis CD. Critical Role of Histone Turnover in Neuronal Transcription and Plasticity. Neuron. 2015 Jul 1; 87(1):77-94. PMID: 26139371 (Highlighted in Neuron).

  9. Maze I, Noh K-M, Soshnev AA, Allis CD. Every amino acid matters: essential contributions of histone variants to mammalian development and disease. Nat Rev Genet. 2014 Apr; 15(4):259-71. PMID: 24614311.


Graduate:

  1. Barton LJ, Lovander KE, Ke W, Luttinger A, Soshnev AA, Geyer PK. Nuclear lamina dysfunction triggers a novel germline stem cell-specific checkpoint. Nat Commun. 2018 Sep 27; 9(1):3960. PMID: 30262885

  2. Barton LJ, Soshnev AA, Geyer PK. Networking in the nucleus: A spotlight on LEM-domain proteins. Curr Opin Cell Biol, 2015 Apr 9; 34:1-8. PMID: 25863918 (Journal cover).

  3. Soshnev AA, Baxley RM, Manak RJ, Tan K, Geyer PK. The insulator protein Suppressor of Hairy-wing is an essential transcriptional repressor in the Drosophila ovary. Development. 2013 Aug 13; 140, 3613-23. PMID: 23884443.

  4. Hohl AM, Thompson M, Soshnev AA, Wu J, Morris J, Shih-Hsieh T, Wu CT, Geyer PK. Restoration of Topoisomerase 2 Function by Complementation of Defective Monomers in Drosophila. Genetics. 2012 Nov; 192(3):843-56. PMID: 22923380.

  5. Soshnev AA, He B, Baxley RM, Jiang N, Hart CM, Tan K, Geyer PK. Genome-wide studies of the multi-zinc finger Drosophila Suppressor of Hairy-wing protein in the ovary. Nucleic Acids Res. 2012 Jul; 40(12):5415-31. PMID: 22406832.

  6. Soshnev AA, Ishimoto H, McAllister BF, Li X, Wehling MD, Kitamoto T, Geyer PK. A conserved long non-coding RNA plays a role in sleep regulation in Drosophila. Genetics 2011 Oct 1; 189(2):455-468. PMID: 21775470 (Highlighted article).

  7. Baxley RM, Soshnev AA, Koryakov DE, Zhimulev IF, Geyer PK. The role of the Suppressor of Hairy-wing insulator protein in Drosophila oogenesis. Dev Biol. 2011 Aug 15; 356(2):398-410. PMID: 21651900 (Journal cover).

  8. Soshnev AA*, Li X*, Wehling MD, Geyer PK. Context differences reveal insulator and activator functions of a Su(Hw) binding region. PLoS Genet. 2008 Aug 15;4(8):e1000159. PMID: 18704163 (*, contributed equally).

  9. Semiglazov VF, Aĭlamazian EK, Baĭliuk EN, Niauri DA, Ivanov VG, Manikhas AG, Kvetnoĭ IM, Soshnev AA. [Prophylaxis of breast cancer in patients with hyperproliferative disorders of the reproductive system] Vopr Onkol. 2006;52(3):247-57. In Russian. PMID: 17191696.

Contact

Alexey A. Soshnev

alexey.soshnev(a)utsa.edu
(210) 458-7950 (office)
(210)
458-7951 (lab)

@alexeysoshnev

Assistant Professor,
Department of Neuroscience, Developmental and Regenerative Biology

University of Texas at San Antonio

BSB 2.03.28

One UTSA Circle

San Antonio, TX 78249

USA

Journal covers

#sciart - some hits and a few misses we are still proud of:

In this issue, Phillips, Soshnev and Allis discuss the epigenetic misregulation in gliomagenesis. Missense mutation of Histone H3 lysine 27 to methionine (H3 K27M) defines a class of pediatric gliomas and has become a textbook example of epigenetic driver in human malignancy. While H3 is encoded by fifteen paralog genes in humans, a single heterozygous mutation is sufficient to dominantly inhibit the enzymatic function of Polycomb Repressor Complex 2. The cover, printed with child wooden alphabet blocks, illustrates the identical amino acid sequences of the multiple copies of H3 (AARKSAPA, pastel colors), and dramatic effect of one missense substitution (M, in black) in this deadly malignancy.
This could have been a cover for our Cancer Cell review on epigenetic misregulation in glioma. It was not selected.
In this issue, Korb et al. (1209–1223) identified a subset of epigenetic regulators as potential targets in Fragile X syndrome. On the cover, the sagittal section of the human brain hemisphere is depicted using paper filigree, with contours of the anatomical structures outlined with artistic representation of the “chromatin fiber.” The repeat units of core histones are shown in canonical red, green, blue, and yellow colors, with linker DNA in teal. The parallel between chromatin architecture and cortical folding highlights the emerging role of epigenetic misregulation in human neurological disorders.
This could have been a cover for Hoffmann and Sanchez-Rivera et al @ Rice/Lowe Labs. It was not selected, but we still like the colors!
The artwork shows increased synaptic contacts on a larger muscle relative to a smaller one, driven by signaling from the growing muscle to the presynaptic motor neuron. The muscles are depicted as buildings, with the larger one receiving more connections from the city grid. Scene is inspired by the authors' experience during the COVID-19 shutdown in New York City.
This could have been a cover for Ho and Treisman from NYU/Skirball. It was not selected.
In this issue, Finkin et al. report that MYC, induced by follicular helper T-cells during affinity maturation in the germinal center, is a critical determinant of B cell division capacity. Rapid cell divisions require a reservoir of essential metabolites to sustain S-G2-M cycling. Light zone MYC expression regulates metabolite accumulation and B cell growth, dictating the subsequent dark zone cell divisions. A mosaic of different size beads represents diverse cellular composition of the germinal center, where largest beads, spelling out “MYC”, are the clones primed for expansion due to MYC accumulation.
This could have been a cover for Finkin et al from Nussenzweig Lab at Rockefeller. It was not selected.
PHF6 controls the phenotypic state of B-cell leukemia cells by regulating the expression of lineage-specific genes. Shown here is a histological analysis of the two distinct lymphoid diseases that are formed in the presence (left) or absence (right) of PHF6. The different ontologies of these malignancies are explained by drastic changes in the expression of genes that regulate the function of normal B and T cells. Mechanistically, PHF6 promotes transcription factor accessibility to B-cell-specific genes in leukemia cells while blocking access to T-cell-specific genes. (For details, see Soto-Feliciano et al., p. 973.)
Hematopoietic stem cells give rise to an array of differentiated cell types that function in innate and adaptive immunity. To serve their respective functions, these cells must in turn respond to a vast number of environmental cues that initiate programs leading to proliferation, differentiation and effector function. The myriad of cell fate decisions that must occur involve changes in gene expression that are mediated by transcription factors, epigenetics, enhancers, genome organization, long non-coding RNAs and post-transcriptional regulation. This volume of Immunological Reviews, guest edited by Amy Weinmann who is an expert in the field, presents a compendium of reviews that seek to put these regulatory mechanisms in perspective.
Revival of trade - exchange of goods - heralded the end of the Dark Ages in Europe, bringing upon the intellectual awaking of the Renaissance. Likewise, global and local histone turnover is shaping cell-type specific functions in the nervous system, critical for neurological plasticity and cognition, disruptions of which result in disease and intellectual decline, as described by Wenderski and Maze. Original artwork based on illumination from the 15th century Trattato de Arithmetica, depicting two merchants engaged in (histone) barter transaction, with histone H3/H4 dimer and nucleosome structures depicted (PDB structures 2HUE and AOI1, respectively).
Shimada et al. demonstrate that linker histone H1-mediated repression of compacted chromatin involves abrogation of histone acetyltransferase p300 enzymatic activity, whereas gene-specific eviction of H1 by p300-bound chaperone NAP1 facilitates p300-dependent core histone acetylation and transcriptional activation. On the cover, histone chaperones and p300 are shown as Lego figures, operating on the repressive (top - grey, black and blue blocks) and active (bottom - red, orange and yellow blocks) chromatin - reminiscent of traditional heat map representation of genomic regions.
This could have been a cover for Shimada et al. from Roeder Lab at Rockefeller. It was not selected.
This could have been a cover for Josefowicz et al. from Allis Lab at Rockefeller. It was not selected.
The cover shows a whole-mount Drosophila ovary, immunostained for fibrillarin (red), Su(Hw) (green) and counterstained with DAPI (blue). Defects in nucleolar structure in su(Hw)f/v ovaries do not affect ribosome biogenesis or oocyte production, implying that the absence of structural reorganization of NC chromosomes is not responsible for sterility of su(Hw) mutant females.
The cover shows a Google Map of the nucleus, highlighting organizational features covered by review articles included in this issue. Zooming into the nuclear periphery it shows features of the nuclear envelope and the contiguous endoplasmic reticulum. Green and red roadways depict chromosomal regions harboring genes of different transcriptional activity. The road construction sign denotes a chromosomal region undergoing DNA repair. Colored squares and circles indicate locations of architectural landmarks or enrichments of organizing proteins, such as chromatin lamina-associated domains (LADs), the nuclear lamina, LEM-domain proteins (LEM-D), Barrier-to-Autointegration Factor (BAF), and Cajal bodies. The wilderness region encompasses the nucleolus. Ferry lines connected to US highways indicate nuclear import and export that includes transit through nuclear pores. The subway symbol (blue square) represents long distance chromosomal loops mediated by protein complexes, such as condensins.
Inspired by the Space Invaders arcade game, the relationship between Torso signaling (aliens), nuclear envelope, and Germ Cell-Less (GCL; laser cannon) is depicted. When the nuclear envelope breaks down (shown on the right), GCL targets Torso for degradation at the plasma membrane, suppressing somatic cell lineages and promoting the formation of primordial germ cells. The background image is a stylized micrograph showing GCL (magenta) at the nuclear envelope in pre-mitotic cells (left) and at the plasma membrane in the dividing cells (right). For more, see Pae et al., pp. 130–142.
Alternative cover for Pae et al (Lehmann Lab at Skirball/NYU). Another version was selected, so we still count it as a win.
A confocal image shows the expression pattern of transcription factors Centrosomal protein 190 (CP190) and Suppressor of Hairy-wing [Su(Hw)]—visible in red and green, respectively—in a fruit fly embryo. Pamela Geyer, PhD, professor of bio-chemistry, and obstetrics and gynecology, uses this model to show how these two proteins collaborate to establish DNA regulatory elements known as chromatin insulators during development, including in the early embryo. Better understanding of chromatin uinsulators could improve strategies for gene therapy and treatment of human disease.
This is not strictly a cover, but still a cool image that ended up printed in Medicine Iowa journal.