Faculty

Alexey Soshnev, M.D., Ph.D.

Assistant Professor

Office: BSB 2.03.28
Phone: (210) 458-7950
Email: Alexey.Soshnev@utsa.edu
Twitter: @alexeysoshnev
Lab website

Areas of Specialization

Chromatin Structure and Function
Gene Regulation in Development and Disease
Histone Biology and Biochemistry

Education

Postdoc; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University
Ph.D. in Molecular and Cellular Biology; The University of Iowa
M.D., St. Petersburg State University Faculty of Medicine, Russia

Research Interests

Aberrant cell fate decisions due to transcriptional misregulation are central to malignant transformation and developmental disorders. Histone proteins are the major constituents of chromatin – complex of nucleic acids and proteins interpreted by cellular machinery, and mutations in histone-encoding genes are increasingly recognized as drivers of disease. Mutations in linker histone genes were recently identified as drivers of peripheral lymphoid malignancy (Yusufova, … Soshnev, Cesarman, Melnick, Nature 2021), and we aim to understand the mechanistic basis of chromatin decompaction, redistribution of core histone modifications, and reactivation of stem cell–specific transcriptional programs upon H1 loss in germinal center B-cells during malignant transformation (refer to Figure 1 for schematic details).

An unusual frameshift mutation in linker histone H1E (H1.4) isoform was recently reported in a number of patients presenting with overgrowth, intellectual disability, and autism spectrum disorder (OG/ID/ASD). While similar syndromes are caused by mutations in a number of related chromatin factors – including core histone methyltransferases NSD1 and PRC2, and DNA methyltransferase DNMT3A – the molecular mechanism remains unclear. Our studies point to a class of transcription factors specifically misregulated by the H1 mutant, and suggest both new mechanisms and new venues for therapeutic intervention in these incurable disorders (see Figure 2 for select preliminary results)

Figure 1

Mechanisms of linker histone H1 function in chromatin and effects of H1 loss
a H1 histone fine-tunes Polycomb and NSD1/2 activities in chromatin. Variant PRC1 (vPRC1), recruited to unmethylated CpG islands by the KDM2B subunit, establishes core histone H2A K119Ub, in turn recruiting the PRC2, responsible for H3 K27 methylation. H1 incorporation stimulates both vPRC1 and PRC2, and opposes the function of NSD1/2 enzymes, which dimethylate H3 K36—a modification implicated in recruitment of DNMT3A DNA methyltransferase to broad intergenic regions and direct inhibition of PRC2 function. Subunit composition of protein complexes is simplified for accessibility; open and filled lollipops indicate unmethylated and methylated CpG sequences, respectively.
b Linker histones integrate chromatin compaction and core histone modifications. Top, schematic distribution of three H3 tail modifications (K9me2/3, K27me3, and K36me2) relative to genome A/B compartment score, with K9me occupying most compact regions, K27me3 found in intermediate regions, and K36me2 demarcating open and highly interactive compartment A. Bottom, while loss of linker histone function universally leads to B-to-A shift, both the degree of decompaction and the trajectories of core histone modifications are distinct and fall into five specific clusters.

Figure 2

Developmental linker histone mutant ectopically interacts with a class of transcription factors in chromatin
a Schematic of H1E protein; location of patient mutations is indicated, with each red lollipop corresponding to an unrelated individual. Below, charged (basic, magenta, and acidic, blue) amino acid residues are mapped onto the wild type and H1E^FS protein structure, and common de novo sequence found in all mutants is indicated. α-H1E^FS antibody used in subsequent experiments was raised against this sequence.
b H1E^FS expression in control (top) and knock-in (bottom) mouse ES cell lines, demonstrating nuclear localization and retention in mitotic chromosomes (arrow-heads); scale bar, 10 μm.
c Heat map representing ATAC-Seq signal at regions demonstrating differential enrichment between two controls and H1E^FS line; median of two replicates is shown. Note increased ATAC signal, indicating increased focal accessibility in H1E^FS.
d motif analyses of differential ATAC peaks returns a single consensus corresponding to basic leucine zipper (bZIP) class of transcription factors.
e Immunoprecipitation of HA-tagged H1E^WT and H1E^FS followed by differential mass-spec analyses of interactors reveals a number of H1E^FS-enriched (red) and depleted (blue) factors; note that bZIP TFs (dark red dots) are among the top H1E^FS interactors.

Training Opportunities

Training of undergraduate, graduate, and post-doctoral personnel have distinct goals and require different approaches. For undergraduate students, our lab offers opportunities for both “wet lab” (primarily histone biochemistry, molecular biology, tissue culture and mouse models, imaging, and "-omics") and "dry lab" (computational approaches) projects, and encourage interested students to contact the lab. For graduate students, please consider whether current research projects and techniques (listed above) are of long-term interest to you, and contact the lab for rotation opportunities. For post-doctoral training, please reach out with specific questions, ideas, and funding opportunities you would like to pursue in the laboratory.

Lab Culture

We are committed to the culture of inclusion and diversity, and aim to promote personal and professional growth of our trainees at all career stages. We are grateful for the opportunity to support trainees from groups historically excluded from science as they pursue their career goals at UTSA, a Hispanic-serving, Carnegie R1 University.

Collaborations

We believe that collaborative science truly reveals the "sum is greater than the parts" principle, and love collaborative projects at all levels. Our current collaborations include laboratories at Weill Cornell Medicine, Sloan Kettering Institute, Rockefeller University, Northwestern University, Albert Einstein College of Medicine, and New York University. If you feel like your studies would benefit from our expertise in histone biology and genome organization, do not hesitate to reach out.