The non-specific lethal (NSL) complex is a chromatin-associated factor that has been shown to manage the expression of 1000’s of genes in each fruit flies and mammals. Abrogation of the NSL genes results in the death of the organism, and this phenotype gives rise to this complex’s curious name. Max Planck researchers have now identified the NSL complex as a “master” epigenetic regulator of intraciliary transport genes across multiple cell types and species. The study reveals that this class of genes is “turned on” by the NSL complex regardless of whether a specific cell has cilia or not. Moreover, the researchers uncovered that this class of cilia-associated genes is actually vitally vital for the function of kidney podocytes, a highly specialized cell type that paradoxically doesn’t carry cilia. These findings have vital implications for ciliopathies and kidney disease.

Cilia are thin, eyelash-like extensions on the surface of cells. They perform a wide range of functions, acting as mechanosensors or chemosensors, and play a vital role in lots of signaling pathways. In the previous couple of a long time, the organelle has undergone a remarkable, but at the identical time sinister, profession transformation. It evolved from an organelle whose relevance was unclear to becoming a central player within the pathogenesis of a big group of diseases. These so-called ciliopathies are related to a wide selection of symptoms, including hearing loss, visual impairment, obesity, kidney disease, and mental disability. Different gene mutations impair cilia formation, maintenance, and performance, leading to these ciliopathies, which may sometimes be multi-organ, syndromic disorders.

The correct assembly, maintenance, and performance of cilia depend on a process called “intraciliary transport”. Components of the intraciliary transport system “walk” on the microtubule to deliver cargo between the cell body and the ciliary tip to make sure a continuing supply of materials. Mutation of genes encoding components throughout the intraciliary transport machinery may lead to ciliopathies. Of their recent study within the journal Science Advances, the lab of Asifa Akhtar identified the NSL complex as a transcriptional regulator of genes known for his or her roles within the intraciliary transport system of cilia across multiple cell types.

The NSL complex enables intraciliary transport

The NSL complex is a potent epigenetic modifier that regulates 1000’s of genes in fruit flies, mice, and humans. Nonetheless, a lot of the functions of the NSL complex remain mysterious and have only recently begun to be elucidated. “Previous research from our lab indicates that the NSL complex controls many pathways critical for organismal development and cellular homeostasis,” says Asifa Akhtar, Director on the MPI of Immunobiology and Epigenetics in Freiburg.

The complex comprises several proteins and is a histone acetyltransferase (HAT) complex that prepares the genes for activation.

Consider gene regulation as a team effort with different players. One vital player is the NSL complex. It puts special marks on the histone proteins on which the DNA is wrapped around within the nucleus, like putting up green flags. These flags tell other regulators to change on specific genes. We now found that the NSL complex does exactly this for a gaggle of genes linked to moving materials inside cilia.”

Tsz Hong Tsang, first writer of the study

Without components of the NSL complex, the cell cannot construct a cilium

The intraciliary transport system is crucial since it is required to construct a functional cilium. The cell uses the intraciliary transport system to maneuver material from the cilium base to the growing tip – just like constructing a tower. Within the study, the researchers used mouse cells to find out the functional consequences of the lack of the NSL complex within the cells.

They found that fibroblast cells lacking the NSL complex protein KANSL2 couldn’t activate the transport genes nor assemble cilia. “As cilia are the sensory and signaling hubs for cells, lack of KANSL2 results in the lack of cells to activate the sonic hedgehog signaling pathway, which plays vital roles within the regulation of embryonic development, cell differentiation, and maintenance of adult tissues in addition to cancer,” says Asifa Akhtar.

Although tiny protrusions, these sensory organelles are incredibly vital to cells. Ciliopathies, which affect organs as diverse because the kidney, liver, eye, ear, and central nervous system, remain difficult for biological and clinical studies. The researchers on the Max Planck Institute in Freiburg hope that their evaluation of the role of the NSL complex has provided vital insights into the regulation of those organelles and the genes related to them, thus contributing to human health.

Consequences of NSL loss in non-ciliated cells

Cilia are present in most cell types within the human body. This explains why ciliopathies can affect so many alternative organs and tissues, but there are also cells that will not be ciliated. Certainly one of the cell types that would not have cilia is mature glomerular podocytes, that are special filtration cells within the kidney. “Interestingly, we found that podocytes also express these intraciliary transport genes which might be regulated by the NSL complex. So, we wondered what would occur in the event that they are unable to change on these genes,” says Tsz Hong Tsang.

The researchers found that in non-ciliated mouse podocytes, the lack of KANSL2 results in changes in microtubule dynamics within the cells. Microtubules are cytoskeletal components answerable for the mechanical stabilization of the cell and intracellular transport between different organelles. While lacking cilia, mature podocytes have specialized cell processes extending from the cell body called primary and secondary processes, whose functions rely heavily on cytoskeletal components. Although apparently milder than the defect in ciliated cells, the Akhtar lab found that the cytoskeletal defects are likely the reason behind severe glomerulopathy and kidney failure observed in mice lacking the NSL complex. These and other extraciliary functions of intraciliary transport genes may help explain the complexity of symptoms presented by ciliopathies.

Source:

Max Planck Institute of Immunobiology and Epigenetics

Journal reference:

Tsang, T. H., et al. (2023) Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells. Science Advances. doi.org/10.1126/sciadv.adh5598.