LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy

Missios, Pavlos; Rocha, Edroaldo Lummertz da; Pearson, Daniel S.; Philipp, Julia; Aleman, Maria M.; Pirouz, Mehdi; Farache, Dorian; Franses, Joseph W.; Kubaczka, Caroline; Tsanov, Kaloyan M.; Jha, Deepak Kumar; Pepe-Mooney, Brian; Powers, John T.; Gregory, Richard I.; Lee, Amy Sy; Domínguez, Daniel; Ting, David T.; Daley, George Q.

doi:10.1172/jci145142

Cited by 14 publications

(20 citation statements)

References 86 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous reports have shown that inflammation-induced emergency megakaryopoiesis can be controlled at the level of protein translation in HSCs. 9 It is thus interesting to note that Lin28A/B controls protein translation independent of its repression of the Let-7 family of microRNAs, 58 , 59 , 60 raising the possibility that Lin28B may restrict lineage-specific protein expression. Indeed, Lin28B can bind to Bcl11a transcripts in human HSPCs to repress protein synthesis and developmental hemoglobin switching.…”

Section: Discussionmentioning

confidence: 99%

Developmental cues license megakaryocyte priming in murine hematopoietic stem cells

et al. 2022

View full text Add to dashboard Cite

The fetal to adult switch in hematopoietic stem cell (HSC) behavior is characterized by alterations in lineage output and entry into deep quiescence. Here we identify the emergence of megakaryocyte (Mk) biased HSCs as an event coinciding with this developmental switch. Single-cell chromatin accessibility analysis reveals a ubiquitous acquisition of Mk lineage priming signatures in HSCs during the fetal to adult transition. These molecular changes functionally coincide with an increased amplitude of early Mk differentiation events following acute inflammatory insult. Importantly, we identify LIN28B - known for its role in promoting fetal-like self-renewal, as an insulator against the establishment of a Mk biased HSC pool. LIN28B protein is developmentally silenced in the third week of life and its prolonged expression delays emergency platelet output in young adult mice. We propose that developmental regulation of Mk priming may represent a switch for HSCs to toggle between prioritizing self-renewal in the fetus and increased host protection in postnatal life.

show abstract

Section: Discussionmentioning

confidence: 99%

Developmental cues license megakaryocyte priming in murine hematopoietic stem cells

et al. 2022

View full text Add to dashboard Cite

show abstract

“…(D) Gene ontology analysis of enriched transcripts. (E) Analysis of overlapping genes between our RIP-targets and previously published LIN28B-mRNA interactome data (22, 31). (F) Plot showing how gene ontology terms identified in D compares and overlaps with LIN28B interacting transcripts identified in the indicated studies.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, our findings implicate the ribosome as a potential target for LIN28B regulation in B cell progenitors. LIN28B enhances protein synthesis in the small Pre-B and Imm-B stages of B cell development LIN28B bound mRNA targets have been linked to both translational increase and decrease in a context dependent manner (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). In the case of ribosomal protein transcripts, enhanced protein translation has been shown by stable isotope labeling using amino acid in culture (22) as well as polysome profiling (31).…”

Section: The Lin28b Mrna Interactome In Primary B Cell Precursors Is ...mentioning

confidence: 99%

“…LIN28B enhances protein synthesis in the small Pre-B and Imm-B stages of B cell development LIN28B bound mRNA targets have been linked to both translational increase and decrease in a context dependent manner (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). In the case of ribosomal protein transcripts, enhanced protein translation has been shown by stable isotope labeling using amino acid in culture (22) as well as polysome profiling (31). To assess ribosomal protein levels during B cell development, we performed western blot analysis on 50,000 sorted B cell precursors from tet-LIN28B and control mice following 10 days of Dox induction in vivo (Supplemental figure 2A).…”

Section: The Lin28b Mrna Interactome In Primary B Cell Precursors Is ...mentioning

confidence: 99%

“…The mechanism for this effect is, although not fully understood, at least in part linked to augmentation of c-MYC protein levels in Imm-B cells and the CD19/PI3K/c-MYC positive feedback loop (19) known to promote B cell positive selection (21). A less understood mechanism of LIN28B action is through the direct binding of coding mRNAs to either positively or negatively regulate transcript stability and protein translation, in a context dependent manner (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). In particular, several studies have demonstrated the ability of LIN28B to promote the translation of ribosomal proteins, through Let-7 independent direct binding to their transcripts in human ES cells (32), transformed human kidney (22) and neuroblastoma (31) cell lines.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Enhanced protein synthesis is a defining requirement for neonatal B cell development

Åkerstrand

Boldrin

Montano

et al. 2022

Preprint

View full text Add to dashboard Cite

Protein synthesis is a stringently regulated process that fundamentally dictates capacity for cellular growth. Rapid fluctuations in cell size and proliferation characterize B cell development. However, little is known about how ribosomal control may impact this process. Here, we identify elevated protein synthesis as a defining feature of early-life B cell development and a determinant for the output of self-reactive CD5+ B-1 cells in mice. Interactome analyses in primary B cell precursors showed direct binding of the heterochronic RNA binding protein LIN28B to ribosomal protein transcripts, which correlated with their elevated protein expression in vivo. Genetic perturbations demonstrated that LIN28B is both necessary and sufficient to elevate protein synthesis during the small Pre-B and immature B cell stages. Interestingly, IL-7 signaling was the dominant driver of the c-MYC/ribosome axis in earlier stages and masked LIN28B induced protein synthesis in Pro-B cells. Finally, we demonstrated that subdued protein synthesis was detrimental for neonatal B cell development and the output of self-reactive B-1 cells, without affecting the adult. Thus, LIN28B elevates ribosomal capacity to shape the naive B cell repertoire in neonatal life.

show abstract

Early Progression of Abdominal Aortic Aneurysm is Decelerated by Improved Endothelial Barrier Function via ALDH2‐LIN28B‐ELK3 Signaling

Yang,

Cui,

Wang

et al. 2023

Advanced Science

View full text Add to dashboard Cite

The involvement of endothelial barrier function in abdominal aortic aneurysm (AAA) and its upstream regulators remains unknown. Single‐cell RNA sequencing shows that disrupted endothelial focal junction is an early (3 days) and persistent (28 days) event during Angiotensin II (Ang II)‐induced AAA progression. Consistently, mRNA sequencing on human aortic dissection tissues confirmed downregulated expression of endothelial barrier‐related genes. Aldehyde dehydrogenase 2 (ALDH2), a negative regulator of AAA, is found to be upregulated in the intimal media of AAA samples, leading to testing its role in early‐stage AAA. ALDH2 knockdown/knockout specifically in endothelial cells (ECs) significantly increases expression of EC barrier markers related to focal adhesion and tight junction, restores endothelial barrier integrity, and suppresses early aortic dilation of AAA (7 and 14 days post‐Ang II). Mechanically, ELK3 acts as an ALDH2 downstream regulator for endothelial barrier function preservation. At the molecular level, ALDH2 directly binds to LIN28B, a regulator of ELK3 mRNA stability, hindering LIN28B binding to ELK3 mRNA, thereby depressing ELK3 expression and impairing endothelial barrier function. Therefore, preserving vascular endothelial barrier integrity via ALDH2‐specific knockdown in ECs holds therapeutic potential in the early management of AAAs.

show abstract

LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy

Cited by 14 publications

References 86 publications

Developmental cues license megakaryocyte priming in murine hematopoietic stem cells

Developmental cues license megakaryocyte priming in murine hematopoietic stem cells

Enhanced protein synthesis is a defining requirement for neonatal B cell development

Early Progression of Abdominal Aortic Aneurysm is Decelerated by Improved Endothelial Barrier Function via ALDH2‐LIN28B‐ELK3 Signaling

Contact Info

Product

Resources

About