Research

All* cells in human body carry the 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 how chromatin compation and chemical modifications are involved in gene regulation. Several ongoing projects are described below - but we are always open to new ideas!

Mechanisms of malignant transformation by linker (H1) histone loss

Linker (H1) histones are small, positively charged, and highly mobile proteins encoded by several paralogous genes in humans. We and others have shown previously that linker histone genes are frequently mutated in lymphomas – a common malignancy arising from peripheral B-cells. H1 mutations result in chromatin decompaction, and redistribution of core histone modifications, including key developmental marks installed by Polycomb Group proteins and Nuclear SET Domain family enzymes. With support from American Cancer Society, CPRIT, and NCI, we continue this work, together with many amazing collaborators in NYC, Chicago, and even France.

People: Dustin Fetch (lead), Tiffany Bastos, Alexey Soshnev

In recent months, Dustin has been pondering whether all histone mutations are created equal, and how we can leverage Big Data to figure it out. Inspired in part by previous work from the Allis, Kurumizaka, Licht, and Nacev labs, we are looking at population genetics of histone mutations. Stay tuned for more!

Chromatin mechanisms of a developmental disorder

A remarkable germline mutation in linker histone H1.4 was reported in a cohort of patients with developmental disorder clinically related to Overgrowth/Intellectual Disability/Autism Spectrum syndromes arising from mutations in DNA methyltransferase DNMT3A (Tatton-Brown-Rahman Sd), H3 K36 dimethylase NSD1 (Sotos Sd) and PRC2 complex (Weaver Sd). Our previous studies in lymphoma suggest that H1 indeed regulates PRC2/NSD1 activity in chromatin, but this case seems different: H1.4 mutation appears to acts by an entirely different, dominant mechanism we are keen to decipher. We think this mutation may offer a unique handle for therapeutic targeting and are pursuing a pilot small molecule study as well.

People involved: Amina Jumamyradova (in vivo studies), Ksenia Dydo (protein purification), Dustin Fetch

How do transcription factors find their place in the genome?

Most TFs occupy significantly fewer binding sites than predicted from sequence alone. E.g., a heterodimer of RUNX1 and CBFβ transcription factors binds a degenerate 7-mer motif (YGYGGTY, where Y is a pyrimidine) occurring hundreds of thousands of times - yet genomic analyses recover orders of magnitude fewer occupied sites. We wonder if local chromatin modifications play a role - and are very excited to figure it out with support from CPRIT High Impact High Risk program and our collaborators at UT Health San Antonio.

People involved: TBD!

Chromatin effects of polyamines in vivo

Polyamines are small, positively charged biomolecules – essential for cell metabolism. Even partial loss of polyamine synthesis enzymes causes massive developmental defects (including premature aging), and enzymes and export machinery are currently under investigation as pharmaceutical targets in many cancers, including pancreatic ductal adenocarcinoma - PDAC. Yet the nuclear role of polyamines is almost entirely unexplored, despite the fact that spermidine is routinely used for chromatin assays in vitro, and chromosomal DNA likely constitutes the largest single target for polyamines in the cell. We are manipulating polyamine levels in cells using genetic and chemical approaches and investigating how these affect chromatin compaction and gene expression.

People involved: Gauri Raje (lead), Tiffany Bastos

Chromatin mechanisms of taste receptor specification

Taste receptor cells arise from epithelium but quickly acquire unique morphological and functional features. We have serendipitously discovered that taste receptor cells have a unique chromatin landscape and are very excited to understand whether this is a cause or consequence of their complex cell fate decision-making. This is a collaborative project with Macpherson lab at UTSA.

People involved: Natalie Redding (lead), Ksenia Dydo

Chromatin mechanisms of pluripotency

Embryonic stem cells cultured in naïve state have remarkably open chromatin – yet canonically repressive histone modification lysine 27 methylation on histone H3 – is greatly expanded. K27me is a “textbook” chromatin compacting modification – so how does more repressive mark coexist with more open chromatin? We have some ideas about that!

People involved: Cameron Chapa

Full disclosure – this page is, essentially, a placeholder. Our research is fairly fluid, and we are excited to start new projects and follow new ideas. Our techniques range from protein purification (we now have a full FPLC and preparative HPLC setup) and biochemistry, to gene editing (and epigenetic manipulation via dCas9) in cell culture, to live imaging, to mouse model and genetics, to genomics (ChIP/CUT&RUN, RNA-Seq, ATAC-Seq) and proteomics. We have collaborations in Texas (UTSA, UT Health SA, UT RGV, Baylor, and UT Houston), all over US (from the Midwest to East Coast), Japan (TDMU) and France (Nantes). We are not afraid to try new tech, and are driven by questions and unknowns, not routine applications of what we are already good at.

Page updated

Google Sites

Report abuse