Biomedical subjects

Sergei Doulatov

Publications and source records attributed to Sergei Doulatov.

3 recordsLinked to original sources

PubMed2026

Splenic extramedullary hematopoiesis in myelofibrosis is shaped by transcriptomic and epigenetic dysregulation.

Myelofibrosis (MF) is a chronic, progressive myeloproliferative neoplasm characterized by bone marrow fibrosis, ineffective blood cell production, and neoplastic extramedullary hematopoiesis (EMH) occurring primarily within the spleen. To explore the molecular mechanisms underlying splenic EMH, we performed single-cell transcriptional and chromatin profiling of cells from MF spleens that had been surgically removed. We demonstrate significant expansion of hematopoietic stem and progenitor cells, coupled with aberrant differentiation toward the erythroid and megakaryocytic lineages, associated with a significant enrichment of inflammatory pathways with enhanced NF-κB signaling and IFN responses, as well as dysregulation of the inferred function of differentiation-defining transcription factors. Finally, we report a significant remodeling of the immune microenvironment in MF spleens, characterized by emergence of dysfunctional T cell subsets and inflammatory memory B cells, suggesting the concomitant establishment of a pro-inflammatory and immune-tolerant tumor microenvironment within the spleen that influences hematopoietic cell differentiation and impairs tumor immune surveillance.

Primary Myelofibrosis↗

PubMed2005

The C-type lectin fold as an evolutionary solution for massive sequence variation.

Only few instances are known of protein folds that tolerate massive sequence variation for the sake of binding diversity. The most extensively characterized is the immunoglobulin fold. We now add to this the C-type lectin (CLec) fold, as found in the major tropism determinant (Mtd), a retroelement-encoded receptor-binding protein of Bordetella bacteriophage. Variation in Mtd, with its approximately 10(13) possible sequences, enables phage adaptation to Bordetella spp. Mtd is an intertwined, pyramid-shaped trimer, with variable residues organized by its CLec fold into discrete receptor-binding sites. The CLec fold provides a highly static scaffold for combinatorial display of variable residues, probably reflecting a different evolutionary solution for balancing diversity against stability from that in the immunoglobulin fold. Mtd variants are biased toward the receptor pertactin, and there is evidence that the CLec fold is used broadly for sequence variation by related retroelements.

Amino Acid Sequence↗

PubMed2004

Tropism switching in Bordetella bacteriophage defines a family of diversity-generating retroelements.

Bordetella bacteriophages generate diversity in a gene that specifies host tropism. This microevolutionary adaptation is produced by a genetic element that combines the basic retroelement life cycle of transcription, reverse transcription and integration with site-directed, adenine-specific mutagenesis. Central to this process is a reverse transcriptase-mediated exchange between two repeats; one serving as a donor template (TR) and the other as a recipient of variable sequence information (VR). Here we describe the genetic basis for diversity generation. The directionality of information transfer is determined by a 21-base-pair sequence present at the 3' end of VR. On the basis of patterns of marker transfer in response to variant selective pressures, we propose that a TR reverse transcript is mutagenized, integrated into VR as a single non-coding strand, and then partially converted to the parental VR sequence. This allows the diversity-generating system to minimize variability to the subset of bases under selection. Using the Bordetella phage cassette as a signature, we have identified numerous related elements in diverse bacteria. These elements constitute a new family of retroelements with the potential to confer selective advantages to their host genomes.

Adaptation, Physiological↗