Li C et al. (2008) WormBook "Neuropeptides."

Kim K, Li C

[WormBook, 2008]

The role of neuropeptides in modulating behavior is slowly being elucidated. With the sequencing of the C. elegans genome, the extent of the neuropeptide genes in C. elegans can be determined. To date, 113 neuropeptide genes encoding over 250 distinct neuropeptides have been identified. Of these, 40 genes encode insulin-like peptides, 31 genes encode FMRFamide-related peptides, and 42 genes encode non-insulin, non-FMRFamide-related neuropeptides. As in other systems, C. elegans neuropeptides are derived from precursor molecules that must be post-translationally processed to yield the active peptides. These precursor molecules contain a single peptide, multiple copies of a single peptide, multiple distinct peptides, or any combination thereof. The neuropeptide genes are expressed extensively throughout the nervous system, including in sensory, motor, and interneurons. In addition, some of the genes are also expressed in non-neuronal tissues, such as the somatic gonad, intestine, and vulval hypodermis. To address the effects of neuropeptides on C. elegans behavior, animals in which the different neuropeptide genes are inactivated or overexpressed are being isolated. In a complementary approach the receptors to which the neuropeptides bind are also being identified and examined. Among the knockout animals analyzed thus far, defects in locomotion, dauer formation, egg laying, ethanol response, and social behavior have been reported. These data suggest that neuropeptides have a modulatory role in many, if not all, behaviors in C. elegans.

Li, Yini et al. (2021) MicroPubl Biol

Li, Yini, Snyder, Matthew, Maine, Eleanor M.

[MicroPubl Biol, 2021]

Histone modifications influence gene expression and chromosome dynamics by altering chromatin structure and recruitment of nonhistone proteins. Dimethylation of histone H3 on lysine 9 (H3K9me2) is a conserved modification often found within heterochromatin. During first meiotic prophase when homologous chromosomes undergo pairing and synapsis, immunolabeling of C. elegans male germ cells detects a relatively high H3K9me2 level on the single X chromosome and a relatively low H3K9me2 level on synapsed autosomes. This H3K9me2 distribution is influenced by several components of the small RNA machinery, including: EGO-1 RNA-directed RNA polymerase (RdRP); DRH-3 helicase; EKL-1, a Tudor domain protein; CSR-1 Argonaute; and RRF-3 RdRP. EGO-1, DRH-3, and EKL-1 function together to generate/stabilize 22G RNAs in the germ line. A subset of these 22G RNAs function together with CSR-1 to ensure correct gene expression. RRF-3 RdRP functions in biogenesis of 26G RNAs that feed into two germline regulatory mechanisms mediated by ERGO-1 Argonaute and the redundant ALG-3 and ALG-4 Argonaute proteins. Here, we report that meiotic H3K9me2 distribution is influenced by ALG-3 and ALG-4, as well as by two other factors required for 26G RNA synthesis, ERI-1 and ERI-5. Moreover, meiotic H3K9me2 distribution is influenced by activity of the poly(U) polymerases, PUP-1 (aka CDE-1, CID-1) and PUP-2.

Li, Yinan et al. (2021) MicroPubl Biol

Kratsios, Paschalis, Li, Yinan

[MicroPubl Biol, 2021]

Terminal selector-type transcription factors are key regulators of neuronal identity and function (Hobert and Kratsios, 2019; Kratsios and Hobert, 2018). Mechanistically, terminal selectors are thought to act directly through binding at the cis-regulatory region of genes (termed "terminal identity genes") that encode, among others, neurotransmitter [NT] synthesis proteins, ion channels, neuropeptides, and cell adhesion molecules (Hobert and Kratsios, 2019; Kratsios and Hobert, 2018). Although dozens of terminal selectors have been described thus far for individual neuron types of the nematode C. elegans (Hobert, 2016), the identification of their target genes has primarily relied on candidate approaches and availability of markers for neuronal terminal identity. Hence, unbiased methods are needed to identify the full spectrum of terminal selector target genes in individual neuron types. This study focuses on the phylogenetically conserved terminal selector UNC-3/Ebf (member of the Collier/Olf/Ebf family), which controls cholinergic motor neuron (MN) identity in the ventral nerve cord of the nematode C. elegans. To identify novel UNC-3 target genes, we took advantage of the genome-wide binding map of UNC-3 from our previous Chromatin Immunoprecipitation followed by Sequencing (ChIP-Seq) analysis (Li et al., 2020). We generated transgenic reporter lines for ten putative terminal identity genes (pxd-1, cal-2, lgc-4, ldb-1, nep-21, D2007.2, dmsr-2, ncs-2, npr-29, drn-1), whose expression patterns were largely unknown in C. elegans. Six of these reporter lines showed expression in ventral nerve cord MNs (nep-21, D2007.2, dmsr-2, ncs-2, npr-29, drn-1), whereas the remaining four (pxd-1, cal-2, lgc-4, ldb-1) showed expression in head and tail neurons, as well as some non-neuronal cells. Importantly, the number of ventral nerve cord MNs showing expression of the nep-21, D2007.2, and dmsr-2 reporters was significantly reduced in unc-3 null mutant animals, thereby expanding the repertoire of known UNC-3 target genes in these cells. Altogether, this study demonstrates that transgenic reporter analysis guided by ChIP-Seq results is a relatively efficient approach for the identification and validation of transcription factor target genes.

Li, Li et al. (2021) International Worm Meeting "Functional analysis of HRPK-1 domains reveals domain and subcellular localization requirements for miRNA-mediated gene expression regulation."

Zinovyeva, Anna, Li, Li

[International Worm Meeting, 2021]

microRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Heterogeneous nuclear ribonucleoproteins (hnRNPs) have recently emerged as factors important for miRNA processing and/or activity. We previously showed that C. elegans HRPK-1 (an hnRNPK homolog) physically interacts with C. elegans Argonaute ALG-1 and genetically interacts with multiple miRNA families, suggesting that HRPK-1 coordinates with miRNA in regulating gene expression. Disruption of HRPK-1 function alters mature miRNA levels, suggesting that HRPK-1 contributes to miRNA processing. To better understand the molecular mechanisms by which HRPK-1 influences gene regulation, we performed a comprehensive functional domain analysis of HRPK-1 protein using CRISPR/Cas9 genome editing. These mutations include inactivation of predicted nuclear localization and exporting signals, PLD domain deletion, and KH domain mutations disrupting HRPK-1 RNA binding activity. We found that all HRPK-1 mutations contribute to HRPK-1 function in coordinating with miRNAs to some extent. For example, mutating the predicted NLS motif abolishes endogenous HRPK-1 expression in the nucleus and enhances the cell fate defect phenotype of lsy-6(ot150) and the heterochronic phenotype of mir-48 mir-241(nDf51), suggesting that the nuclear localization is required for HRPK-1 function with regards to miRNA-mediated gene regulation. We will describe our data on HRPK-1 domain requirements and present models on how HRPK-1 may modulate miRNA activity. Our investigation of HPRK-1 functional domains furthers our understanding of how hnRNP proteins may coordinate with miRNAs in gene expression regulation.

Li J et al. (2008) Oncogene "Caspases in apoptosis and beyond."

Li J, Yuan J

[Oncogene, 2008]

The demonstration of protein sequence and functional homology of the Caenorhabditis elegans programmed cell death gene product, CED-3, with human caspase-1 in 1993 triggered an explosion of research activities toward the understanding of molecular mechanisms of apoptosis. During the past 15 years, a plethora of knowledge has been obtained on the mammalian caspases, the homologs of CED-3, with regard to their distinct physiological functions, their substrates, different activation mechanisms, the signal transduction pathways that lead to their activation as well as their involvement in the pathogenesis of diseases. Such knowledge is beginning to be translated into new therapies for the treatment of human diseases.

Li WQ et al. (1992) Worm Breeder's Gazette "Promoting her-1"

Wood WB, Perry MD, Li WQ

[Worm Breeder's Gazette, 1992]

The her-1 gene is required for normal male development in C. elegans. Previous work (Trent et al. M.o.D. 34:43,1991; Perry et al., C. elegans Mtg. Abstr. 1992, p.230) has shown that the gene includes four exons and gives rise to a rare larger and an abundant smaller transcript as shown below. To confirm that these RNA's have different promoters as suggested by RNase protection assays (Robertson et al., this issue) and to analyze their activities, we made reporter constructs by fusing the LacZ gene to each of two DNA fragments containing putative promoter regions (see below): a) the 2.5 kb 5' flanking region of exon 1 (putative P1 ),and b) the entire 3.4 kb intron 2 (putative P2 ).Each of the constructs was co-injected with cloned rol-6 (su1006)DNA into a him-8 (e1489)strain, which produces about 40% XO progeny. Stable transformant lines were obtained and stained with X-gal. For the P1 construct, no -galactosidase activity has been detected in the embryos, possibly because of the weakness of this promoter. For the P2 construct, staining is observed in up to 40% of the embryos, from about the 30-cell stage onward. Most cells are stained, suggesting that expression is not limited to certain cell lineages. These results prove the presence of a second promoter in the her-1 locus. When an integrated P2 construct was crossed into an N2 background to determine its activity in XX embryos, no -galactosidase activity was detected except in a few cells in late embryos. This result is also consistent with RNase-protection results (ibid.). When the same construct was introduced into the her-1 deletion strain him-8 (e1489);her-1 (y101hv1)(all hermaphrodites, but 40% XO), it showed staining similar to that seen in the him-8 (e1489)strain. We conclude that P2 activity is XO-specific and is independent of her-1 expression. We also tried to detect P1 activity by observing its biological function, transforming the him-8 ;her-1 strain with a construct (c) carrying the putative P1 region, the four exons, and only the first intron. Transformed animals produced strongly masculinized progeny including fertile males, indicating that the large transcript can be sufficient for male development. [See Figure 1]

Li R (2013) Dev Cell "The art of choreographing asymmetric cell division."

Li R

[Dev Cell, 2013]

Asymmetric cell division (ACD), a mechanism for cell-type diversification in both prokaryotes and eukaryotes, is accomplished through highly coordinated cell-fate segregation, genome partitioning, and cell division. Whereas important paradigms have arisen from the study of animal embryonic divisions, the strategies for choreographing the dynamic subprocesses are, in fact, highly varied. This review examines divergent mechanisms of ACD across different kingdoms. Examples discussed show that there is no obligatory hierarchy among the dynamic events and that asymmetry can emerge from each event, but cell polarization more often occurs as the initial instructive process for patterning ACD especially in the multicellular context.

Li Y (2011) Protein Cell "Systematic temperature signaling regulates behavior plasticity."

Li Y

[Protein Cell, 2011]

Li, yujie et al. (2011) International Worm Meeting "Coordination of Arls in cilia."

zhang, yuxia, Wei, Qing, Hu, Jinghua, Li, yujie

[International Worm Meeting, 2011]

Joubert syndrome (JS) is the most common inherited cerebellar malformation disorder that belonging to a rapidly expanding group of human diseases called ciliopathies. All identified JS loci encode cilia-related proteins, however, with the precise roles enigmatic. Small GTPase Arl13B was identified as one JS locus. Here, we report the function of ARL-13, the sole C. elegans ortholog of human Arl13B, in regulating cilia biogenesis. In C. elegans, ARL-13 specifically localizes to ciliary doublet segment in its proline-rich C-terminus dependent manner. arl-13 animals exhibit shortened cilia with various cilia ultrastructural defects as well as disrupted association between intraflagellar transport (IFT) subcomplex A and B. Intriguingly, depletion of ARL-3, another evolutionarily conserved ciliary small GTPase, can suppress ciliogenesis defects in arl-13(lf) via a microtubule associated deacetylase HDAC-6 dependent pathway by restoring the binding efficiency between IFT subcomplex A and B. BBS proteins are a group of proteins mutated in another human ciliopathy Bardet-Biedl syndrome. It was reported that IFT-A and IFT-B dissociate in several worm bbs mutants. By checking BBS-7 and BBS-8 in arl-13 null worms, we found BBS proteins move with integrate IFT particles, but not with dissociated IFT-A or IFT-B subcomplex. These observations suggest the gene products encoded by different ciliopathy loci can have a functional crosstalk in same cellular process involved in ciliogenesis.

Li J et al. (2021) Autophagy "Conserved role of ENDOG in promoting autophagy."

Zhou Q, Li J, Wang W

[Autophagy, 2021]

ENDOG (endonuclease G), a mitochondrial endonuclease, is known to participate in apoptosis and paternal mitochondria elimination. However, the role and underlying mechanism of ENDOG in regulating macroautophagy remain unclear. We recently reported that ENDOG released from mitochondria promotes autophagy during starvation, which we demonstrated is evolutionarily conserved across species by performing experiments in human cell lines, mice, <i>Drosophila</i>, and <i>C. elegans</i>. This study demonstrates that ENDOG can be phosphorylated by GSK3B, which enhances the interaction between ENDOG with YWHAG and leads to the release of TSC2 and PIK3C3 from YWHAG, followed by MTOR pathway suppression and autophagy initiation. Additionally, the endonuclease activity of ENDOG is essential for activating the DNA damage response and thus inducing autophagy. Consequently, this study uncovered an exciting new role for ENDOG as a crucial regulator of autophagy.