Research Areas
Research in the Casero Laboratory focuses on the application of computational techniques to illuminate the discovery of novel signaling pathways in hematopoiesis, immunity and inflammation. We rely on the design of novel methodologies for the analysis of multidimensional, sequencing-based databases using basic studies on both mouse and human hematopoietic progenitor cells, along with translational studies for biomarker discoveries in both cancer and inflammatory diseases.
Long Non-Coding RNAs in Development and Signal Transduction
Figure 1. Identification of lineage- or differentiation-stage–specific lncRNA gene–protein-coding gene co-expression modules. From Long non-coding RNA profiling of human lymphoid progenitor cells reveals transcriptional divergence of B cell and T cell lineages. Casero D, Sandoval S, Seet CS, Scholes J, Zhu Y, Ha VL, Luong A, Parekh C, Crooks GM. Nat Immunol. 2015;16:1282–1291.
Previous work in human hematopoietic progenitors has been focused on the discovery of novel non-coding developmental regulators with potential to participate in cell fate decisions. In particular, long non-coding RNAs (lncRNAs) have emerged as a leading class of regulatory elements in multiple biological processes. In collaboration with the Crooks Lab, the Casero Lab contributed the first genome-wide catalog of lncRNAs in human bone marrow hematopoietic stem cells and early lymphoid progenitors in vivo. This work provided a reference resource of novel hematopoietic-related lncRNAs that may have a regulatory role in human development and disease.
Additional collaborative work with the Rao Lab, yielded the identification of an lncRNA-specific signature in patients with B-lymphoblastic leukemia, and the mechanisms of action of the CASC15 lncRNA in a subset of patients with childhood acute lymphoblastic leukemia. With Peter Tontonoz, MD, PhD, and Tamer Sallam, MD, PhD, the Casero Lab contributed to the mechanisms of action of certain lncRNAs in cholesterol metabolism.
Current research activity in this field aims to:
- Expand knowledge on the mechanisms of action of lncRNAs at specific stages of stem cell development using high-throughput screens
- Analyze the effect of mRNA modifications (epitranscriptomics) on lncRNA activity
- Incorporate lncRNA expression signatures in genome-wide association studies
Classification of Gene Expression Signatures in the Context of Aging and Chronic Inflammation
A better understanding of how changes in the cellular microenvironment of certain tissues (e.g., thymus, gut) affect molecular and differentiation pathways in immune cells constitutes a predominant theme of our research program. Further research in this field will be instrumental to identify novel biomarkers in, among others, childhood hematologic malignancies or immune dysfunctions in late adulthood (chronic inflammation). For instance, aging significantly alters the pattern of blood cell production in the bone marrow and, in particular, is known to result in reduced lymphopoiesis and increased myelopoiesis. Although, how changes in the bone marrow microenvironment influence these events are not fully understood.
Figure 2. Gene expression changes during the transition from PSC to hEMP to CD8SP T cells. From Organoid-induced differentiation of conventional T cells from human pluripotent stem cells. Montel-Hagen A, Seet CS, Li S, Chick B, Zhu Y, Chang P, Tsai S, Sun V, Lopez S, Chen HC, He C, Chin CJ, Casero D, Crooks GM. Cell Stem Cell. 2019 Mar 7;24(3):376-389.e8.
The Casero Laboratory continues studies on hematopoietic progenitors and the regulatory and signaling pathways involved in both B- and T-cell development. In collaboration with the laboratory of Ken Dorshkind, PhD, the Casero Lab has previously delineated the regulatory networks involved in age-dependent waves of B1 and B2 B-cells development, and distinct waves of fetal and adult T-cell development. We have also recently described the molecular and regulatory hallmarks of myeloid skewing in the aged murine bone marrow, and demonstrated that aged hematopoietic stem cells retain normal differentiation capacity upon removal from the inflammatory milieu. The Casero Lab was later able to place plasma cells at the center of a regulatory network that includes stromal cells and macrophages, which together play an obligate role in age-related abnormal hematopoiesis.
A paramount example of the influence of an aged microenvironment on the onset of disease in adulthood is thymic involution. Signals from the thymic mesenchyme are lost soon after birth and limit the breadth and quality of the T-cell output and, therefore, of human immunity. Together, the Casero Lab and Crooks Lab are defining the main pathways that are altered in each thymic compartment upon depletion of essential developmental signals in both mice and humans. We hope these studies will pave the way toward the discovery of novel biomarkers for thymic rejuvenation.
Current work in this area include:
- The application of single-cell profiling to fully understand the effect that signals from the aged microenvironment have on the intrinsic phenotype of hematopoietic progenitors
- The integration of single-cell, whole-tissue and tissue organoid gene expression profiles for the identification of intrinsic (cell-specific), relational (controlled by the microenvironment) or systemic (tissue-specific) molecular signatures in stem and immune cell biology
- The establishment of the association between different classes of molecular signatures (intrinsic/relational/tissue-specific) and additional biomarkers from multi-omics datasets to identify pathogenic factors in inflammatory bowel disease (IBD)
Host-Microbiome Interactions
Figure 2. Metabolic network modeling and taxa-metabolite associations. From Space-type radiation induces multimodal responses in the mouse gut microbiome and metabolome. Casero D, Gill K, Sridharan V, Koturbash I, Nelson G, Hauer-Jensen M, Boerma M, Braun J, Cheema AK. Microbiome. 2017 Aug 18;5(1):105.
In many relevant cases, signals from our microbiome constitute an additional layer of regulation in the establishment and maintenance of normal tissue homeostasis. This additional layer requires a conceptual shift from the activities described above: now the normal microenvironment (self) also interacts with its symbiotic gut microbiota (quasi-self) and possibly pathogens (non-self). A proper understanding of these interactions is instrumental to gain insights into the etiology of some complex diseases, with IBD being a paradigmatic example.
As members of the Inflammatory Bowel and Immunobiology Research Institute at Cedars-Sinai, the Casero Lab is harnessing the power of multi-omics libraries to generate novel data-driven hypotheses that can pave the way into future mechanistic and translational studies. We are currently implementing computational strategies for the analysis of multidimensional high-throughput data, with a focus on reverse-engineering signaling at the onset of microbiome-mediated chronic inflammatory diseases.
Ongoing activities include:
- The longitudinal analysis and integration of metaproteomics data with metagenomics and metatranscriptomics samples from the Integrative Human Microbiome Project
- The effect of mucosal integrity on host-microbiome interactions and host-specific responses
- Exploring the role of lncRNAs in the modulation of host-microbiome interactions